Cyclic amines

ABSTRACT

The present invention is directed to novel cyclic amines which inhibit the P2X 7  receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Non-Provisional patentapplication Ser. No. 14/793,773, filed on Jul. 8, 2015 (issued on Aug.16, 2016 as U.S. Pat. No. 9,415,055), which application is acontinuation of U.S. Non-Provisional patent application Ser. No.14/050,466 (filed on Oct. 10, 2013, and issued on Aug. 18, 2015 as U.S.Pat. No. 9,108,938), which application claims the benefit of U.S.Provisional Patent Appln. No. 61/713,099 (filed Oct. 12, 2012, nowlapsed).

FIELD OF THE INVENTION

The present invention is directed to novel compounds which inhibit theP2X₇ receptor. Separate aspects of the invention are directed topharmaceutical compositions comprising said compounds and uses of thecompounds to treat pain, inflammation, neurological disorders, orneuropsychiatric disorders.

BACKGROUND ART

The purinergic 2X₇ (P2X₇) receptor is a ligand-gated ion channel whichis activated by extracellular ATP and is present on a variety of celltypes, including microglia in the central nervous system and other cellsinvolved in inflammation and immune system function. The P2X₇ receptorhas been shown to have a role in cytolysis in the immune system(Surprenant, et al. Science, 272, 735-41, 1996), and is involved inactivation of lymphocytes and monocyte/macrophages leading to theincreased release of pro-inflammatory cytokines (e.g., TNFα and IL1β)from these cells (Ferrari, et al. Neuropharmacol, 36, 1295-301, 1997).

Studies have shown that inhibiting P2X₇ receptor activation insituations of inflammation (e.g., rheumatoid arthritis and otherautoimmune diseases, osteoarthritis, asthma, chronic obstructivepulmonary disease and inflammatory bowel disease) or interstitialfibrosis results in a therapeutic effect (DiVirgilio, et al. Drug DevRes, 45, 207-13, 1998). These and other studies indicate that P2X₇receptor antagonists may find use in the treatment and prophylaxis ofpain, including acute, chronic and neuropathic pain (Chessel, et al,Pain, 114, 386-96, 2005).

Inhibiting P2X₇ activation may also diminish or reduce cell death causedby prolongation of activated P2X₇ receptors, indicating a potentialtherapeutic intervention for said antagonists in nervous system injuryor degeneration (Sperlagh, et al., Progress in Neurobiology, 7, 327-346,2006). Vianna, et al. (Epilepsia, 43, 27-229, 2002) also revealed apotential role for P2X₇ receptors in the pathogenesis of epilepsy.Interestingly, because of the P2X₇ receptor's role in microgliaactivation and proliferation in the central nervous system (CNS), aself-propagating cycle of neuroinflammation and neurodegenerationresults from P2X₇ receptor activation in areas of the brain (Monif, etal, J Neurosci, 29, 3781-91, 2009).

Thus, P2X₇ receptor antagonists, particularly small molecules withsufficient brain-penetrable properties, are desirable as useful agentsfor therapeutic intervention in the central nervous system for treatingpain, inflammation, neurological and neurodegenerative disorders,neuropsychiatric disorders, or other disorders for which the reductionor otherwise stabilization of pro-inflammatory cytokines is beneficial.The present invention fulfills this need, and provides further relatedadvantages.

SUMMARY OF THE INVENTION

An objective of the present invention is to provide compounds thatinhibit P2X₇ receptors. Accordingly, the present invention relates tocompounds of Formula I.

-   -   wherein R¹ is phenyl, pyridyl , pyrazinyl, pyridazinyl,        pyrimidyl or 5 membered heteroaryl, each of which is optionally        substituted with one or more C₁₋₆alkyl, halogen, hydroxy, C₁₋₄        fluoroalkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, C₁₋₆fluoroalkoxy, cyano        or —SO₂R⁷;    -   wherein R^(2a) and R^(2b) combine with the nitrogen to which        they are attached to form piperazinyl, piperidinyl, morpholinyl,        pyrrolidinyl, pyrrolo, imidazo, azetidinyl, 6 to 10 membered        spiro(heterocyclyl), homomorpholinyl, homopiperidinyl or        homopiperazinyl each of which is optionally substituted with one        or more C₁₋₆alkyl, C₁₋₆alkenyl, C₃₋₆-cycloalkyl, C₁₋₆alkoxy,        oxo, —NR⁵R⁶ or fluorine;    -   wherein R³ is halogen, C₁₋₄fluoroalkyl, cyano, cyclopropyl,        C₁₋₄alkyloxy, C₁₋₄fluoroalkyloxy, —SO₂R⁷, —NR⁵R⁶ or C₁₋₆alkyl;    -   wherein R⁴ is halogen, C₁₋₆alkyl, C₁₋₄fluoroalkyl, cyano,        —SO₂R⁸, —NR⁵R⁶, C₁₋₆alkoxy, C₁₋₄ fluoroalkoxy or        C₃₋₆-cycloalkyl;    -   wherein R⁵ and R⁶ independently of each other are hydrogen or        C₁₋₆alkyl;    -   wherein R⁷ is C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₄fluoroalkyl; and    -   wherein n is 0-3; or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of the invention or a pharmaceutically acceptable salt thereof,and optionally a pharmaceutically acceptable carrier, excipient ordiluent.

The compounds of Formula I may contain one or more stereogenic orasymmetric centers, such as one or more asymmetric carbon atoms. Thecompounds of Formula I may thus be present as mixtures of stereoisomersor preferably as pure stereoisomers. Mixtures of stereoisomers can beseparated in a manner known to a person skilled in the art.

The present invention further provides methods for treating pain orinflammation in a subject, comprising administering to a subjectsuffering from pain or inflammation a therapeutically effective amountof a compound of Formula I.

The present invention further provides methods for treating an affectivedisorder in a subject comprising administering to a subject sufferingfrom an affective disorder a therapeutically effective amount of atleast one compound of Formula I.

The present invention further provides methods for treating aneurological disorder or neurodegenerative disorder in a subjectcomprising administering to a subject suffering from a neurologicaldisorder or neurodegenerative disorder a therapeutically effectiveamount of at least one compound of Formula I.

The present invention further provides methods for treating depression,major depressive disorder, treatment resistant depression, anxiety,obsessive-compulsive disorder, post-traumatic stress disorder (PTSD),neuropathic pain, osteoarthritis, rheumatoid arthritis, psoriaticarthritis, inflammatory bowel disease, multiple sclerosis, epilepsy,Parkinson's Disease, Huntington's Disease and Alzheimer's disease, whichinvolves administering a compound of Formula I.

The present invention also provides the use a compound of Formula I forthe manufacture of a medicament for the treatment of affectivedisorders.

The present invention also provides a compound of Formula I for use intreating an affective disorder in a subject.

These and other aspects of the invention will become apparent uponreference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As previously indicated, the present invention is based on the discoveryof the compounds of Formula I, which are inhibitors of the P2X₇receptor, and as such, are useful for the treatment of relateddisorders. Additionally, certain aspects of the invention are explainedin greater detail below but this description is not intended to be adetailed catalog of all the different ways in which the invention may beimplemented, or all the features that may be added to the instantinvention. Hence, the following specification is intended to illustratesome embodiments of the invention, and not to exhaustively specify allpermutations, combinations and variations thereof.

In one embodiment, R¹ is optionally substituted phenyl.

In one embodiment, R¹ is optionally substituted pyridyl.

In another embodiment, R¹ is optionally substituted pyrazinyl.

In one embodiment, R¹ is optionally substituted pyrimidyl.

In one embodiment, R¹ is optionally substituted 5 membered heteroaryl.

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted piperazinyl.

In yet embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted piperidinyl.

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted morpholinyl.

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted pyrrolidinyl.

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted pyrrolo.

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted imidazo.

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted 6 to 10 memberedspiro(heterocyclyl).

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted homomorpholinyl

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted homopiperidinyl

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted homopiperazinyl

In one embodiment, R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted azetidinyl.

In one embodiment, R³ is chlorine, methyl or trifluorormethyl.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, n is 2.

In one embodiment, R⁴ is fluorine, chlorine, C₁₋₃alkyl, C₁₋₄fluoroalkyl,cyano, C₁₋₃alkoxy or C₁₋₄fluoroalkoxy.

As used herein, the term “C₁-C₆ alkyl” refers to a straight chained orbranched saturated hydrocarbon having from one to six carbon atomsinclusive. Examples of such substituents include, but are not limitedto, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl, 2-methyl-1-propyl, n-pentyl and n-hexyl. Similarly,the term “straight chained or branched C₁-C₃ alkyl” refers to asaturated hydrocarbon having from one to three carbon atoms inclusive.Examples of such substituents include, but are not limited to, methyl,ethyl and n-propyl.

Likewise, the term “C₁-C₆ alkoxy” refers to a straight chained orbranched saturated alkoxy group having from one to six carbon atomsinclusive with the open valency on the oxygen. Examples of suchsubstituents include, but are not limited to, methoxy, ethoxy, n-butoxy,t-butoxy and n-hexyloxy.

As used herein, the term “C₁-C₄ fluoroalkyl” refers to a straightchained or branched saturated hydrocarbon having from one to four carbonatoms inclusive substituted with one or more fluorine atoms. Examples ofsuch substituents include, but are not limited to, trifluoromethyl,pentafluoroethyl, 1-fluoroethyl, monofluoromethyl, difluoromethyl and1,2-difluoroethyl.

Likewise, the term “C₁-C₄ fluoroalkoxy” refers to a straight chained orbranched saturated alkoxy group having from one to four carbon atomsinclusive with the open valency on the oxygen and in which one or morecarbon atoms are substituted with one or more fluorine atoms. Examplesof such substituents include, but are not limited to, monofluoromethoxy,1,1-difluoroethoxy and 1-monofluoro-n-butoxy.

Likewise the term “C₃₋₆ cycloalkyl” refers to saturated monocyclichydrocarbon groups. Examples of such systems include, but are notlimited to, cyclopropyl, cyclobutyl or cyclohexyl

Likewise the term “5 membered heteroaryl” refers to a fully unsaturatedaromatic monocyclic ring system having 1-4 heteroatoms. Examples of suchsystems include, but are not limited to, thienyl, furyl, imidazolyl andpyrrolyl.

Likewise the term “6 to 10 membered spiro(heterocyclyl)” refers to aheterocyclic ring which is a fused bicyclic system. Examples of suchsystems include, but are not limited to, 2-oxa-6-aza-spiro[3.3]heptane,2-aza-spiro[3.3]heptane and 2,6-diaza-spiro[3.3]heptane.

The term “halogen” refers to fluorine, chlorine, bromine and iodine.

As used herein, the phrase “effective amount” when applied to a compoundof the invention, is intended to denote an amount sufficient to cause anintended biological effect. The phrase “therapeutically effectiveamount” when applied to a compound of the invention is intended todenote an amount of the compound that is sufficient to ameliorate,palliate, stabilize, reverse, slow or delay the progression of adisorder or disease state, or of a symptom of the disorder or disease.In an embodiment, the method of the present invention provides foradministration of combinations of compounds. In such instances, the“effective amount” is the amount of the combination sufficient to causethe intended biological effect.

The term “treatment” or “treating” as used herein means ameliorating orreversing the progress or severity of a disease or disorder, orameliorating or reversing one or more symptoms or side effects of suchdisease or disorder. “Treatment” or “treating”, as used herein, alsomeans to inhibit or block, as in retard, arrest, restrain, impede orobstruct, the progress of a system, condition or state of a disease ordisorder. For purposes of this invention, “treatment” or “treating”further means an approach for obtaining beneficial or desired clinicalresults, where “beneficial or desired clinical results” include, withoutlimitation, alleviation of a symptom, diminishment of the extent of adisorder or disease, stabilized (i.e., not worsening) disease ordisorder state, delay or slowing of a disease or disorder state,amelioration or palliation of a disease or disorder state, and remissionof a disease or disorder, whether partial or total, detectable orundetectable.

Pharmaceutically Acceptable Salts

The present invention also comprises salts of the present compounds,typically, pharmaceutically acceptable salts. Such salts includepharmaceutically acceptable acid addition salts. Acid addition saltsinclude salts of inorganic acids as well as organic acids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic,lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic,picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic,tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,theophylline acetic acids, as well as the 8-halotheophyllines (forexample, 8-bromotheophylline and the like). Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in S. M. Berge, etal., J. Pharm. Sci., 1977, 66, 2.

Furthermore, the compounds of this invention may exist in unsolvated aswell as in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol and the like.

Racemic forms may be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Separation of such diastereomericsalts can be achieved, e.g. by fractional crystallization. The opticallyactive acids suitable for this purpose may include, but are not limitedto d- or l-tartaric, mandelic or camphorsulfonic acids. Another methodfor resolving racemates into the optical antipodes is based uponchromatography on an optically active matrix. The compounds of thepresent invention may also be resolved by the formation andchromatographic separation of diastereomeric derivatives from chiralderivatizing reagents, such as, chiral alkylating or acylating reagents,followed by cleavage of the chiral auxiliary. Any of the above methodsmay be applied either to resolve the optical antipodes of the compoundsof the invention per se or to resolve the optical antipodes of syntheticintermediates, which can then be converted by methods described hereininto the optically resolved final products which are the compounds ofthe invention.

Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jaques, A. Collet and S. Wilen in Enantiomers, Racemates, andResolutions, John Wiley and Sons, New York, 1981. Optically activecompounds can also be prepared from optically active starting materials.

Pharmaceutical Compositions

The present invention further provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula Iand a pharmaceutically acceptable carrier. The present invention alsoprovides a pharmaceutical composition comprising a therapeuticallyeffective amount of one of the specific compounds disclosed in theExperimental Section and a pharmaceutically acceptable carrier.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by an oral route. Pharmaceutical compositions for oraladministration include solid dosage forms such as capsules, tablets,dragees, pills, lozenges, powders and granules. Where appropriate, thecompositions may be prepared with coatings such as enteric coatings orthey may be formulated so as to provide controlled release of the activeingredient such as sustained or prolonged release according to methodswell known in the art. Liquid dosage forms for oral administrationinclude solutions, emulsions, suspensions, syrups and elixirs.

The term “inhibit” or “inhibiting” as used herein means to reduce,diminish, block or even eliminate, such as in e.g. “inhibiting P2X₇receptor activity”. “Inhibiting P2X₇ receptor activity” or “inhibitingP2X₇ activity” as used herein means, e.g. reducing or even eliminatingthe ability of a P2X₇ receptor to exhibit a cellular response, such asinhibiting the response to stimuli or agonist ligands, or inhibiting theproduction or accumulation of IL1β.

The present invention also provides a method of treating a disease ordisorder, the method comprising administering a therapeuticallyeffective amount of at least one compound of the present invention or apharmaceutically acceptable salt thereof to a mammal suffering from (orat risk for) the disease or disorder, or otherwise in need of thetreatment. The present invention also provides a method of treating painor inflammation, the method comprising administering a therapeuticallyeffective amount of at least one compound of the present invention or apharmaceutically acceptable salt thereof to a mammal in need thereof. Inan embodiment, the pain that may be treated using the compoundsdescribed herein, including acute, chronic or inflammatory pain, iscaused by neuropathic pain, post-operative pain, morphine tolerance,fibromyalgia, neuralgias, headache, osteoarthritis, rheumatoidarthritis, psoriatic arthritis, irritable bowel syndrome or inflammatorybowel disease.

In other embodiments, the disease or disorder that may be treated usingthe compounds described herein is a neurological disorder orneurodegenerative disorder, such as epilepsy, multiple sclerosis,Parkinson's disease, Huntington's disease or Alzheimer's disease. Asused herein, the term “neurological disorder” means a disorder of thenervous system, and includes, but is not limited to, the disorders asdescribed hereinabove. Based on the well-known meaning of disorders ofthe nervous system, neurological disorders result from structural,biochemical, electrical, or cellular (neuronal or microglial) signalingabnormalities that may occur in the brain or spinal cord of theafflicted mammal. As used herein, the term “neurodegenerative disorder”means a disorder characterized by symmetrical and progressive loss ofstructure or function of neurons, such as death of neurons or reducedgrowth of neurons. Such loss of neurons may affect motor, sensory, orcognitive neuronal systems. As such, treating a neurological orneurodegenerative disorder using the compounds described herein mayresult in the amelioration or relief of symptoms of the neurological orneurodegenerative disorder, such symptoms as paralysis, muscle weakness,poor coordination, uncontrolled movements, seizures, confusion, alteredlevels of consciousness, memory loss, emotional instability, loss ofsensation, pain, and similar symptoms.

In an embodiment, the disease or disorder is a neuropsychiatricdisorder, such as an affective disorder. As used herein, “affectivedisorder” means a mental disorder characterized by a consistent,pervasive alteration of mood, and affecting thoughts, emotions andbehaviors. Affective disorders include mood disorders as described inDSM-IV-TR® (American Psychiatric Association, 2000, Diagnostic andStatistical Manual of Mental Disorders (4th ed., text rev.)doi:10.1176/appi.books.9780890423349; which is incorporated by referenceherein). As such, treating an affective disorder using the compoundsdescribed herein may result in the amelioration, stabilization orotherwise diminishment or relief of symptoms of the affective disorder,such symptoms as mood instability, manic episodes, feelings of guilt orworthlessness, sleep disturbances, agitation, or the like. Examples ofaffective disorders include, but are not limited to, depressivedisorders, anxiety disorders, bipolar disorders, dysthymia andschizoaffective disorders. Anxiety disorders include, but are notlimited to, generalized anxiety disorder, panic disorder,obsessive-compulsive disorder, phobias, and post-traumatic stressdisorder (PTSD). Depressive disorders include, but are not limited to,major depressive disorder (MDD), catatonic depression, melancholicdepression, atypical depression, psychotic depression, postpartumdepression, treatment-resistant depression, bipolar depression,including bipolar I and bipolar II, and mild, moderate or severedepression. Personality disorders include, but are not limited to,paranoia, antisocial and borderline personality disorders.

In an embodiment of the invention, the affective disorder treated usingthe compounds described herein is depression, major depressive disorder(MDD), treatment-resistant depression, bipolar disorder, generalizedanxiety disorder, panic disorder, obsessive-compulsive disorder, orpost-traumatic stress disorder (PTSD), or a combination thereof.

The present invention provides a method of treating an affectivedisorder in a subject, comprising administering to a subject in need ofsuch treatment a therapeutically effective amount of at least onecompound of Formula I.

The present invention provides a method of inhibiting P2X₇ activity in asubject, comprising administering to a subject in need thereof atherapeutically effective amount of at least one compound of Formula I.

The present invention also provides a method of inhibiting production oraccumulation of IL1β, comprising administering to a subject in need ofsuch treatment a therapeutically effective amount of at least onecompound of Formula I.

In an embodiment, the present invention provides the use of a compoundof Formula I for the manufacture of a medicament for the treatment ofaffective disorders. The present invention also provides the use of acompound of Formula I for the manufacture of a medicament for theinhibition of P2X₇ activity. The present invention further provides theuse of a compound of Formula I for the manufacture of a medicament forthe inhibition of production or accumulation of IL1β.

In an embodiment, the present invention provides at least one compoundof Formula I for use in treating an affective disorder in a subject. Inan embodiment, the present invention provides at least one compound ofFormula I for use in inhibiting P2X₇ activity in a subject. In anembodiment, the present invention provides at least one compound ofFormula I for use in inhibiting production or accumulation of IL1β in asubject.

The invention also provides a compound of Formula I for use in therapyof a subject, for example, in the treatment of affective disorders.

EXPERIMENTAL SECTION

The compounds of the present invention of the general formula I, whereinR¹, R^(2a), R^(2b), R³, R⁴ and n are as defined above can be prepared bythe methods outlined in the following reaction scheme 1 and in theexamples. In the described methods, it is possible to make use ofvariants or modifications, which are themselves known to chemistsskilled in the art or could be apparent to the person of ordinary skillin this art. Furthermore, other methods for preparing compounds of theinvention will be readily apparent to the person skilled in the art inlight of the following reaction schemes and examples.

The schemes may involve the use of selective protecting groups duringthe synthesis of the compounds of the invention. One skilled in the artwould be able to select the appropriate protecting group for aparticular reaction. It may be necessary to incorporate protection andde-protection strategies for substituents such as amino, amino,carboxylic acid and hydroxyl groups in the synthetic methods describedbelow to synthesize the compounds of Formula I. Methods for protectionand de-protection of such groups are well known in the art, and may befound in T. Green, et al., Protective Groups in Organic Synthesis, 1991,2^(nd) Edition, John Wiley & Sons, New York.

General Methods

Analytical LC-MS data were obtained using one of the methods identifiedbelow.

Method A: Performed using electrospray ionization (ESI) operating inpositive mode via a Waters ZQ (Waters Corp.) mass spectrometer (all fromWaters Corp., Milford, Mass., USA), an Agilent 1100 LC pump (AgilentTechnologies, Inc., Santa Clara, Calif.), and Agilent 1100 autosampler,with a 200 μl/min split to the ESI source with inline Agilent 1100 diodearray detector (DAD) and variable wavelength detector (VWD) at 254 nm,and an 800 uL/min split to a Waters evaporative light scatteringdetector (ELSD). Separation was performed on a Inertsil ODS-3 3 μm50×4.6 mm column using a mobile phase of A) water 1% acetonitrile and0.2% ammonium formate; and B) Acetonitrile, which was delivered in agradient fashion over 1.70 minutes going from 20% B to 85% B. Thenstepped to 100% B at 1.85 minutes and maintained at 100% B until 1.99minutes.

Method B: A PE Sciex API 150EX instrument equipped with atmosphericpressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC system wasused. Column: 3.0×30 mm Waters Symmetry C18 column with 2.2 μm particlesize; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/trifluoroacetic acid (99.965:0.035); Method: Lineargradient elution with A:B=90:10 to 20:80 in 1.5 minutes and with a flowrate of 1.2 mL/min.

Method C: A PE Sciex API 150EX instrument equipped with atmosphericpressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC system wasused. Column: 3.0×30 mm Waters Symmetry C18 column with 2.2 μm particlesize; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/trifluoroacetic acid (99.965:0.035); Method: Lineargradient elution with A:B=100:0 to 70:30 in 1.5 minutes and with a flowrate of 1.2 mL/min.

Method D: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEHC18 1.7 μm; 2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutes and witha flow rate of 1.2 mL/min.

Method E: An Agilent 1200 LCMS system with ELS detector was used.Column: Agilent TC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method F: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEHC18 1.7 μm; 2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=98:2 to 0:100 in 1.0 minutes and with aflow rate of 1.2 mL/min.

Method G: An Agilent 1200 LCMS system with ELS detector was used.Column: Agilent TC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=90:10 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method H: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEHC18 1.7 μm; 2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/formic acid (99.9:0.1) and B=acetonitrile/water/formic acid(94.9:5:0.1); Method: Linear gradient elution with A:B=90:10 to 0:100 in1.0 minutes and with a flow rate of 1.2 mL/min.

Method I: An Agilent 1200 LCMS system with ELS detector was used.Column: Waters XBridge Sheild RP18 5 μm; 2.1×50 mm; Column temperature:40° C.; Solvent system: A=water/ammonia (99.95:0.05) and B=acetonitrile;Method: Linear gradient elution with A:B=95:5 to 0:100 in 4.0 minutesand with a flow rate of 0.8 mL/min.

Preparative LC-MS-purification was performed on a PE Sciex API 150EXinstrument with atmospheric pressure chemical ionization. Column: 50×20mm YMC ODS-A with 5 μm particle size; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=80:20 to 0:100 in 7 minutes and with aflow rate of 22.7 mL/minute. Fraction collection was performed bysplit-flow MS detection.

Preparative SFC was performed on a Thar 80 instrument. Exemplifiedconditions can be, but not limited to: Column AD 250×30 mm with 20 μmparticle size; Column temperature: 38° C., Mobile phase: SupercriticalCO₂/EtOH (0.2% NH₃H₂O)=45/55.

¹H NMR spectra were recorded at 300, 400, 500 or 600 MHz on BrukerAvance instruments. TMS was used as internal reference standard.Chemical shift values are expressed in ppm. The following abbreviationsare used for multiplicity of NMR signals: s=singlet, d=doublet,t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet,dt=double triplet, dq=double quartet, tt=triplet of triplets,m=multiplet, br s=broad singlet and br=broad signal.

Benzoic acids of formula II are commercially available or available bymethods described in the literature (see for example Shaikh, TanveerMahammad Ali, J. Org. Chem (2006), 71, 5043-5046 and Mongin, Florence;Tetrahedron Lett. (1996), 37, 6551-6554).

Abbreviations are in accordance with to the ACS Style Guide: “The ACSStyle guide—A manual for authors and editors” Janet S. Dodd, Ed. 1997,ISBN: 0841234620

Preparation of Intermediates

2-Trifluoromethyl-pyrimidine-5-carbaldehyde

To a solution of ethyl 2-trifluoromethyl-pyrimidine-5-carboxylate (1 g,5 mmol) in DCM (23 mL) at −78° C. was added DIBAL-H (6 ml, 6 mmol, 1.0 Msolution in toluene) slowly and stirred at the same temperature for 3 h.The mixture was quenched with slow addition of 2M hydrochloric acid andwarmed to room temperature. The mixture was extracted with EtOAc (3×20mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated to give the title compound (572 mg, yield:71.5%). ¹H NMR (CDCl₃ 400 MHz): δ ppm 10.27 (s, 1H), 9.35 (s, 2H).

Morpholin-4-yl-(2-trifluoromethyl-pyrimidin-5-yl)-acetonitrile

To a mixture of 2-trifluoromethyl-pyrimidine-5-carbaldehyde (572 mg,3.25 mmol) and TMSCN (645 mg, 6.49 mmol) in HOAc (10 ml) was addeddropwise morpholine (311 mg, 3.57 mmol), followed by NaOAc (320 mg, 3.90mmol). The mixture was stirred at room temperature overnight. Thesolvent was removed in vacuum. The residue was basified by addition ofsat. aq. NaHCO₃ solution to pH 8; then extracted with EtOAc (3×10 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and evaporated to yield the title compound (591mg, yield: 67%). ¹H NMR (CDCl₃ 400 MHz): δ ppm 9.10 (s, 2H), 4.96 (s,1H), 3.88-3.71 (m, 4H), 2.79-2.55 (m, 4H).

2-Morpholin-4-yl-2-(2-trifluoromethyl-pyrimidin-5-yl)-ethylamine

A mixture ofmorpholin-4-yl-(2-trifluoromethyl-pyrimidin-5-yl)-acetonitrile (200 mg,0.735 mmol), Raney-Ni (200 mg), NH₃ (aq) (1.5 mL) in MeOH (20 mL) wasdegassed and purged with Ar and H₂ each 3 times. The mixture was stirredat room temperature under H₂ (30 psi) for 25 minutes. The resultingmixture was filtered and the filtrate was concentrated under reducedpressure to yield the title compound (175 mg, yield: 86%). ¹H NMR (CDCl₃40 MHz): δ ppm 8.83 (s, 2H), 3.80-3.61 (m, 4H), 3.44 (t, J=5.2 Hz, 1H),3.19-2.99 (m, 2H), 2.52-2.35 (m, 4H).

The following intermediates were prepared in a similar way:

-   2-Morpholin-4-yl-2-pyridin-2-yl-ethylamine;-   2-Morpholin-4-yl-2-pyridin-3-yl-ethylamine;-   2-Morpholin-4-yl-2-pyridin-4-yl-ethylamine;-   2-(4-Fluoro-phenyl)-2-morpholin-4-yl-ethylamine;-   2-(4-Chloro-phenyl)-2-morpholin-4-yl-ethylamine;-   2-(4-Methoxy-phenyl)-2-morpholin-4-yl-ethylamine;-   2-(4-Methyl-phenyl)-2-morpholin-4-yl-ethylamine;-   2-(4-Methoxy-phenyl)-2-piperidin-1-yl-ethylamine;-   2-Azetidin-1-yl-2-(4-chloro-phenyl)-ethylamine;-   2-(6-Cyclopropyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine;-   2-Morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine;-   2-(6-Chloro-pyridin-3-yl)-2-morpholin-4-yl-ethylamine;-   2-Morpholin-4-yl-2-pyrimidin-5-yl-ethylamine;-   2-(2-Methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine;-   2-(6-Methyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine;-   2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine;-   2-(4-Fluoro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine;-   2-(4,4-Difluoro-piperidin-1-yl)-2-(4-methoxy-phenyl)-ethylamine;-   2-(4,4-Difluoro-piperidin-1-yl)-2-(6-fluoro-pyridin-3-yl)-ethylamine;-   2-(4,4-Difluoro-piperidin-1-yl)-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine;-   2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;-   2-(4,4-dimethylpiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;-   2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;-   2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;-   2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethanamine;-   2-(2-methylpyrimidin-5-yl)-2-(piperidin-1-yl)ethanamine;-   2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethanamine;-   2-(4-methoxypiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(4-chlorophenyl)-2-(1,4-oxazepan-4-yl)ethanamine;-   2-(3-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine;-   2-(2-methylpyrimidin-5-yl)-2-(3-methylpyrrolidin-1-yl)ethanamine;-   2-(2-methylpyrimidin-5-yl)-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)ethanamine;-   2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(2-isopropylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(2-azabicyclo[2.2.1]heptan-2-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   2-(2-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;-   5-(2-amino-1-(4,4-difluoropiperidin-1-yl)ethyl)-N,N-dimethylpyrimidin-2-amine;-   5-(2-amino-1-(4,4-difluoropiperidin-1-yl)ethyl)-1-methylpyridin-2(1H)-one;-   1-(2-Amino-1-(2-methylpyrimidin-5-yl)ethyl)piperidin-4-ol;-   2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;    2-Cyclopropylpyrimidine-5-carbaldehyde

To a three-neck flask (1000 mL) was added dry DMF (85 mL) and POCl₃ (103g, 0.67 mol) was added drop-wise at room temperature. After the additionwas completed, the mixture was stirred for 30 minutes and malonic acid(20 g, 0.19 mol) was added in portions over 40 minutes, keeping theinner temperature below 25° C. The resulting mixture was heated to 90°C. for overnight. The reaction mixture was cooled to room temperatureand added into stirring ice-water (80 mL) containing NaClO₄ (53 g, 0.38mol) in portions, keeping the inner temperature at 0° C. The suspensionwas filtered; the solid was dried in air to give intermediate a1, whichwas used in the next step without further purification.

To a mixture of a1 (ca. 0.095 mol) in CH₃CN (300 mL) was addedcyclopropanecarboximidamide hydrochloride (12.5 g, 0.105 mol), thensodium hydroxide (7.6 g, 0.19 mol) in water (7.6 mL) was added drop-wiseat 0° C. After addition was complete, the resulting mixture was stirredat room temperature overnight. After filtration, the filtrate wasconcentrated to remove CH₃CN under reduced pressure and the residuewater phase was extracted with DCM (3×300 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuum to give a redoil, which was purified by column chromatography on silica gel(petroleum ether: EtOAc=2:1) to afford2-cyclopropylpyrimidine-5-carbaldehyde (7.6 g, yield: 53.5%). ¹H NMR(CDCl3 400 MHz): δ 10.06 (s, 1H), 8.99 (s, 2H), 2.41-2.35 (m, 1H),1.32-1.21 (m, 4H).

2-(2-Cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile

To a solution of 2-cyclopropylpyrimidine-5-carbaldehyde (2 g, 13.5 mmol)and TMSCN (2.68 g, 27 mmol) in AcOH (30 mL) was added4,4-difluoropiperidine hydrochloride (3.1 g, 13.5 mmol), followed byAcONa (2.66 g, 32.4 mg). The mixture was stirred at 30° C. forovernight. The solvent was removed under reduced pressure and saturatedNaHCO₃ (aq) was added to the mixture to pH=8. The resulting mixture wasextracted with EtOAc (3×100 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuum to give the2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrileas a light red solid (3.5 g, 93%), which was used directly for next stepwithout further purification. ¹H NMR (CDCl3 400 MHz): δ 8.69 (s, 2H),4.88 (s, 1H), 2.73-2.70 (t, J=5.5 Hz, 4H), 2.34-2.27 (m, 1H), 2.11-2.00(m, 4H), 1.19-1.13 (m, 4H).

2-(2-Cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine

A mixture of2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile(3.50 g, 126 mmol), Raney Ni (3.50 g) and NH₃.H₂O (10 mL) in MeOH (150mL) was degassed and purged with argon and H₂, then stirred at roomtemperature under H₂ (50 Psi) for 4 hours. The reaction mixture wasfiltered and concentrated in vacuum to give2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamineas a yellow oil (3.10 g), which was used directly for next step withoutfurther purification.

(4-Chloro-phenyl)-pyrrolidin-1-yl-acetonitrile

To a solution of 4-Chlorobenzaldehyde (2.50 g, 17.8 mmol) intetrahydrofuran (15 mL) was added TMSCN (2.4 mL, 18.0 mmol) and Zincdiiodide (30.0 mg, 0.094 mmol) at 0° C. The mixture was stirred at 0° C.for 15 min. To the mixture was added pyrrolidine (1.50 mL, 18.0 mmol) atroom temperature. The resultant mixture was stirred at room temperatureovernight.

All of the volatiles were removed by rotary evaporator. The residue wasdissolved in dichloromethane (100 mL) and was washed with saturatedsodium bicarbonate (aq). The organic solution was dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (petroleum ether: EtOAc=1:0 to 1:1) toafford (4-Chloro-phenyl)-pyrrolidin-1-yl-acetonitrile (3.52 g, yield:85%). ¹H NMR (CDCl₃ 400 MHz): δ 7.48 (d, 2H), 7.39 (d, 2H), 5.02 (s,2H), 2.67 (m, 2H), 2.61 (m, 2H), 1.84 (m, 4H).

2-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethanamine

To a solution of (4-Chloro-phenyl)-pyrrolidin-1-yl-acetonitrile (3.52 g,15.2 mmol; in Tetrahydrofuran (96 mL) was added Lithiumtetrahydroaluminate (1225 mg, 32.28 mmol) and the reaction was refluxedover night. The reaction was quenched with H₂O (1.22 ml), 2M NaOH (aq)(1.22 ml) and H₂O (2.44 ml). The solid was filtered off and the reactionwas concentrated, to yield2-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethanamine (1.14 g, 30% yield).

The following intermediates were prepared in a similar way:

-   2-(3-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine    Bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS)

To a vessel equipped with a stir bar, Zn dust (1.8 g, 27.8 mmol) wasadded H₂O (20 mL). The reaction vessel was then capped, wrapped inaluminum foil and cooled in an ice bath to 0° C. Difluoromethanesulfonylchloride (5 g, 33.3 mmol) was then added via syringe open to air. Thereaction vessel was sealed with cap and the reaction mixture was removedfrom the ice bath and allowed to warm to room temperature over 2 h. Theexcess Zn was removed via filtration, washed with EtOAc (3×10 mL), thefiltrate was concentrated under reduced pressure. Residual water wasremoved azeotropically with toluene (3×10 mL) at 45° C., and theresulting pearly yellow powder was further dried under vacuum for anadditional 3 h to give bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) (4g, yield:81.6%), which was used in the next step without purification.¹H NMR (DMSO-d₆ 400 MHz): δ 5.24 (t, J=56.0 Hz, 1H).

2-Morpholino-2-(pyrimidin-5-yl)acetonitrile

To a mixture of pyrimidine-5-carbaldehyde (2 g, 18.52 mmol) and TMSCN(3.67 g, 37.0 mmol) in HOAc (50 mL) was added morpholine (2.42 g, 27.8mmol) at room temperature and NaOAc (3.34 g, 40.7 mmol) was followed.The resulting mixture was stirred at room temperature overnight.Saturated aqueous Na₂CO₃ solution was added to quench the reactionmixture, the pH was adjusted to about 7 and extracted with EtOAc (3×100mL). The combined organic layer was washed with brine, dried over Na₂SO₄and concentrated to give crude2-morpholino-2-(pyrimidin-5-yl)acetonitrile (2.5 g, yield: 66%). ¹H NMR(CDCl₃ 400 MHz): δ 9.25 (s, 1H), 8.92 (d, J=10.0 Hz, 2H), 4.87 (s, 1H),3.79-3.70 (m, 4H), 2.67-2.56 (m, 4H).

2-(2-(Difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile

To a solution of 2-morpholino-2-(pyrimidin-5-yl)acetonitrile (1.03 g,5.04 mmol) and DFMS (4 g, 13.61 mmol) in DCM (40 mL) and H₂O (16 mL) atroom temperature was added CF₃COOH (575 mg, 5.04 mmol) followed by slowaddition of 2-hydroperoxy-2-methylpropane (3.24 g, 70% solution in H₂O)with vigorous stirring. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was portioned between DCM(50 mL) and saturated NaHCO₃ solution (50 mL), the organic layer wasseparated and the aqueous layer was extracted with DCM (5 mL×3). Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The crude product was purified by Prep-TLC (Petroleumether:EtOAc=10:1˜2:1) to give2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile (150 mg,yield: 11.7%). ¹H NMR (CDCl₃ 400 MHz): δ 9.01 (d, J=10.0 Hz, 2H), 6.67(t, J=54.4 Hz, 1H), 4.91 (s, 1H), 3.95-3.62 (m, 4H), 2.81-2.46 (m, 4H).

2-(2-(Difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine

A mixture of2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile (150 mg,0.59 mmol), Raney-Ni (75 mg), NH₃.H₂O (2 mL) in MeOH (20 mL) wasdegassed and purged with Ar and H₂ each 3 times. The mixture was stirredat room temperature under H₂ (50 psi) for 3 h. The resulting mixture wasfiltered through celite. The filtrate was concentrated under reducedpressure to give crude2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine, which wasused in the next step without further purification.

The following intermediates were prepared in a similar way:

-   2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine;-   2-(6-(difluoromethyl)pyridin-5-yl)-2-morpholinoethanamine;-   2-(6-(difluoromethyl)pyridin-3-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine;    5-Bromopyrimidine-2-carbonitrile

To a solution of NaCN (0.849 g, 17.32 mmol) and DABCO (0.390 g, 3.48mmol) in a mixture of DMSO (4 ml) and H₂O (9 ml) was added a solution of5-bromo-2-chloropyrimidine (3.05 g, 15.75 mmol) in DMSO (9 ml). Thesolution was stirred at room temperature overnight, and then dilutedwith water, and extracted with EtOAc. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated to give5-bromopyrimidine-2-carbonitrile (2.327 g, 12.01 mmol, 76% yield, 1H NMR(CDCl₃ 500 MHz): δ 8.94 (s, 2H)).

1-(5-Bromopyrimidin-2-yl)ethanone

To a solution of 5-bromopyrimidine-2-carbonitrile (221 mg, 1.2 mmol) inTHF (10 ml) was added methylmagnesium bromide (3.0 ml, 4.20 mmol, 1.4molar, THF) at −78° C. under nitrogen. The solution was stirred at −78°C. for 3.5 hours, and then quenched with satd aq NH₄Cl, and extractedwith EtOAc. The combined organic layer was dried over anhydrous Na₂SO₄and concentrated. The reaction was purified by column chromatography onsilica gel (petroleum ether: EtOAc=1:0 to 0:1) to afford1-(5-bromopyrimidin-2-yl)ethanone (155 mg, 61% yield). ¹H NMR (CDCl₃ 500MHz): δ 9.00 (s, 2H), 2.80 (s, 3H).

5-Bromo-2-(1,1-difluoroethyl)pyrimidine

1-(5-bromopyrimidin-2-yl)ethanone (304 mg, 1.514 mmol) in anhydrous DCM(50 ml), under nitrogen, was treated w Diethylaminosulfur trifluoride(1220 mg, 1 ml, 7.57 mmol). After 12 hours of stirring additionalDiethylaminosulfur trifluoride (610 mg, 0.5 ml, 3.75 mmol) was added.This was repeated again after 24 hours, Diethylaminosulfur trifluoride(610 mg, 0.5 ml, 3.75 mmol). After 36 hours the reaction was quenchedwith sat. NaHCO₃ and extracted with AcOEt, washed with Brine and driedover Na₂SO₄, filtered and concentrated. The reaction was purified bycolumn chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1)to afford 5-bromo-2-(1,1-difluoroethyl)pyrimidine (298 mg, 88% yield).¹H NMR (CDCl₃ 500 MHz): δ 8.92 (s, 2H), 2.08 (t, 2H).

2-(1,1-Difluoroethyl)-5-vinylpyrimidine

PdOAc₂ (22 mg, 0.1 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (53 mg, 0.13mmol) (DavePhos), cesium carbonate (880 mg, 2.70 mmol) and potassiumtrifluoro(vinyl)borate (145 mg, 1.1 mmol) were mixed. THF (10 ml), water(3 ml) and 5-bromo-2-(1,1-difluoroethyl)pyrimidine (200 mg, 0.897 mmol)was added. Degassed for 20 minutes, with argon. The resulting mixturewas capped and heated to 100° C., for 30 min in microwave oven. Thereaction mixture was partitioned between EtOAc (20 mL) and H₂O (10 mL).The aq. layer extracted with EtOAc (2×10 mL) and the combined organiclayers washed with brine (10 mL), dried (Na₂SO₄) and concentrated. Thereaction was purified by column chromatography on silica gel (petroleumether: EtOAc=1:0 to 0:1) to afford2-(1,1-difluoroethyl)-5-vinylpyrimidine (114 mg, 75% yield). ¹H NMR(CDCl₃ 500 MHz): δ 8.88 (s, 2H), 6.73 (m, 1H), 6.02 (d, 1H), 5.61 (d,1H), 2.10 (t, 2H).

2-(1,1-Difluoroethyl)pyrimidine-5-carbaldehyde

2-(1,1-difluoroethyl)-5-vinylpyrimidine (110 mg, 0.646 mmol) wasdissolved in THF (5 ml) and water (2 ml). NaIO₄ (571 mg, 2.67 mmol),2,6-lutidine (143 mg, 0.155 ml, 1.3 mmol) and osmium tetraoxide (138 mg,0.17 ml, 0.013 mmol, 0.078 molar in tBuOH) was added. The reactionmixture was stirred at room temperature for 2 hours. Water was added andthe mixture was extracted with diethyl ether. The organic phase waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. ¹H NMRshowed a mixture of aldehyde and lutidine, which was used directly inthe next reaction, (166 mg, 42% yield, 28% pure). ¹H NMR (CDCl₃ 500MHz): δ 10.24 (s, 1H), 9.30 (s, 2H), 2.12 (t, 2H).

2-(2-(1,1-Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile

To a solution of 2-(1,1-difluoroethyl)pyrimidine-5-carbaldehyde (166 mg,0.270 mmol, 28%) in THF (4 ml) was added TMS cyanide (79 mg, 0.1 ml, 0.8mmol) and zinc iodide (2.2 mg, 6.89 μmol). The mixture was stirred for15 min. To the mixture was added 4,4-difluoropiperidine hydrochloride(62 mg, 0.393 mmol) and DIPEA (37 mg, 0.05 ml, 0.286 mmol). Theresultant mixture was stirred at room temperature overnight. Thevolatiles were removed by rotary evaporator and the reaction waspurified by column chromatography on silica gel (petroleum ether:EtOAc=1:0 to 0:1) to afford2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile(as a 1:1 mixture of nitrile and aldehyde) (39 mg, 24% yield). ¹H NMR(CDCl₃ 500 MHz): δ 9.03 (s, 2H), 5.02 (s, 1H), 2.76 (m, 4H), 2.10 (m,6H).

2-(2-(1,1-Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine

2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile(39 mg, 0.065 mmol, 50%) was dissolved in ammonia (2034 μl, 4.07 mmol, 2molar in MeOH) and hydrogenated on H-Cube, by passing the solution overthe Ra-Ni catcart 3 times at 60° C. and 60 bar. The solution wasconcentrated to afford2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine,which was used crude in the next reaction.

Compounds of formula I can be prepared by employing standard amide bondforming coupling procedures by the reaction of a carboxylic acid offormula II with an amine of formula III.

This reaction is typically carried out in a solvent such as THF or DMF,employing peptide coupling reagents exemplified by, but not limited toEDC and HOBt in the presence of a tertiary amine base such astriethylamine or diisopropylethylamine (DIPEA), at a temperature rangingfrom about 10° C. to about 30° C. Other non-limiting examples ofcoupling reagents include carbonyldiimidazole,N,N′-dicyclohexylcarbodiimide orbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate asreported by Coste et al. Tetrahedron Lett. (1990) 31 (2): 205. Or

Compounds of formula I can be prepared by employing standard amide bondforming coupling procedures by the reaction of a carboxylic acidchloride of formula IV with an amine of formula III.

This reaction is typically carried out in a solvent such as THF, DCM orDMF in the presence of a tertiary amine base such as triethylamine ordiisopropylethylamine (DIPEA), at a temperature ranging from about 10°C. to about 30° C.

Preparation of the Compounds of the Invention EXAMPLE 1a

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-pyridin-2-yl-ethyl)-benzamide

A mixture of (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine (62.2 mg, 0.3mmol), 2-chloro-5-methylbenzoic acid (54 mg, 0.315 mmol), PyBOP (187 mg,0.36 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL) was stirred atroom temperature overnight. The mixture was purified by preparative HPLCto yield the title compound (100 mg, yield: 90%). LCMS (MH⁺): m/z=360.0,t_(R) (minutes, Method A)=0.89

The following compounds were synthesised in a similar way as to example1a:

EXAMPLE 1b

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

From 2-chloro-5-methylbenzoic acid and(2-morpholin-4-yl-2-pyridin-3-ylethyl)amine. LCMS (MH⁺): m/z=360.0,t_(R) (minutes, Method A)=0.77

EXAMPLE 1c

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

From 2-chloro-5-methylbenzoic acid and(2-morpholin-4-yl-2-pyridin-4-ylethyl)amine. LCMS (MH⁺): m/z=360.0,t_(R) (minutes, Method A)=0.77

EXAMPLE 1d

2-Methyl-N-(2-morpholin-4-yl-2-pyridin-2-yl-ethyl)-benzamide

From 2-methylbenzoic acid and(2-morpholin-4-yl-2-pyridin-2-ylethyl)amine. LCMS (MH⁺): m/z=326.1,t_(R) (minutes, Method A)=0.76

EXAMPLE 1e

2-Methyl-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

From 2-methylbenzoic acid and(2-morpholin-4-yl-2-pyridin-3-ylethyl)amine. LCMS (MH⁺): m/z=326.0,t_(R) (minutes, Method A)=0.62

EXAMPLE 1f

2-Methyl-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

From 2-methylbenzoic acid and(2-morpholin-4-yl-2-pyridin-4-ylethyl)amine. LCMS (MH⁺): m/z=326.1,t_(R) (minutes, Method A)=0.62

EXAMPLE 1g

2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin-2-yl-ethyl)-benzamide

From 2,3-dichlorobenzoic acid and(2-morpholin-4-yl-2-pyridin-2-ylethyl)amine. LCMS (MH⁺): m/z=380.1,t_(R) (minutes, Method A)=0.83

EXAMPLE 1h

2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

From 2,3-dichlorobenzoic acid and(2-morpholin-4-yl-2-pyridin-3-ylethyl)amine. LCMS (MH⁺): m/z=379.9,t_(R) (minutes, Method A)=0.79

EXAMPLE 1i

2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

From 2,3-dichlorobenzoic acid and(2-morpholin-4-yl-2-pyridin-4-ylethyl)amine. LCMS (MH⁺): m/z=379.9,t_(R) (minutes, Method A)=0.79

EXAMPLE 1j

2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin-2-yl-ethyl)-benzamide

From 2,3-dimethylbenzoic acid and(2-morpholin-4-yl-2-pyridin-2-ylethyl)amine. LCMS (MH⁺): m/z=340.1,t_(R) (minutes, Method A)=0.83

EXAMPLE 1k

2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

From 2,3-dimethylbenzoic acid and(2-morpholin-4-yl-2-pyridin-3-ylethyl)amine. LCMS (MH⁺): m/z=340.1,t_(R) (minutes, Method A)=0.73

EXAMPLE 1l

2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

From 2,3-dimethylbenzoic acid and(2-morpholin-4-yl-2-pyridin-4-ylethyl)amine. LCMS (MH⁺): m/z=340.0,t_(R) (minutes, Method A)=0.73

EXAMPLE 1m

2,3-Dichloro-N-[2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=396.9,t_(R) (minutes, Method A)=1.22

EXAMPLE 1n

2,3-Dichloro-N-[2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethylamine. LCMS (MH⁺): m/z=407.0,t_(R) (minutes, Method A)=1.28

EXAMPLE 1o

2,3-Dichloro-N-[2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=408.9,t_(R) (minutes, Method A)=1.17

EXAMPLE 1p

N-[2-(4-Fluoro-phenyl)-2-morpholin-4-yl-ethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=357.0,t_(R) (minutes, Method A)=1.16

EXAMPLE 1q

N-[2-(4-Methoxy-phenyl)-2-piperidin-1-yl-ethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethylamine. LCMS (MH⁺): m/z=367.1,t_(R) (minutes, Method A)=1.09

EXAMPLE 1r

N-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl-ethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=369.0,t_(R) (minutes, Method A)=1.10

EXAMPLE 1s

2-Chloro-N-[2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-5-methyl-benzamide

From 2-chlorobenzoic acid and2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=376.9,t_(R) (minutes, Method A)=1.21

EXAMPLE 1t

2-Chloro-N-[2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethyl]-5-methyl-benzamide

From 2-chlorobenzoic acid and2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethylamine. LCMS (MH⁺): m/z=387.0,t_(R) (minutes, Method A)=1.19

EXAMPLE 1u

2-Chloro-N-[2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethyl]-5-methyl-benzamide

From 2-chlorobenzoic acid and2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=388.9,t_(R) (minutes, Method A)=1.16

EXAMPLE 1v

N-[2-(4-Fluoro-phenyl)-2-morpholin-4-yl-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=343.0,t_(R) (minutes, Method A)=1.07

EXAMPLE 1w

N-[2-(4-Methoxy-phenyl)-2-piperidin-1-yl-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethylamine. LCMS (MH⁺): m/z=353.0,t_(R) (minutes, Method A)=0.96

EXAMPLE 1x

N-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=355.0,t_(R) (minutes, Method A)=1.01

EXAMPLE 1y

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-p-tolyl-ethyl)-benzamide

From 2-chloro-5-methylbenzoic acid and2-(4-methyl-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=373.0,t_(R) (minutes, Method A)=1.18

EXAMPLE 1z

N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine. LCMS(MH⁺): m/z=392.9, t_(R) (minutes, Method A)=1.62

EXAMPLE 1a1

N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine. LCMS(MH⁺): m/z=407.0, t_(R) (minutes, Method A)=1.68

EXAMPLE 1b1

N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethyl]-2,3-dichloro-benzamide

From 2,3-dichlorobenzoic acid and2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine. LCMS(MH⁺): m/z=446.8, t_(R) (minutes, Method A)=1.73

EXAMPLE 2a

2,3-Dichloro-N-[2-(4,4-difluoro-1-piperidyl)-2-(6-fluoro-3-pyridyl)ethyl]benzamide

A mixture of2-(4,4-difluoro-piperidin-1l-yl)-2-(6-fluoro-pyridin-3-yl)-ethylamine(100 mg, 0.38 mmol), 2,3-dichlorobenzoic acid (51 mg, 0.28 mmol), HOBT(57 mg, 0.42 mmol), EDC.HCl (81 mg, 0.42 mmol) and DIPEA (108 mg, 0.84mmol) in DMF (4 mL) was stirred at room temperature overnight. Themixture was purified by preparative HPLC directly to yield the titlecompound (43 mg, yield: 30%) LCMS (MH⁺): m/z=432.0, t_(R) (minutes,Method E)=2.33

The following compounds were synthesised in a similar way:

EXAMPLE 2b

2,3-Dichloro-N-[2-(4-chloro-phenyl)-2-morpholin-4-yl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=412.8,t_(R) (minutes, Method D)=0.54

EXAMPLE 2c

2,3-Dichloro-N-[2-(6-cyclopropyl-pyridin-3-yl)-2-morpholin-4-yl-ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(6-cyclopropyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺):m/z=412.8, t_(R) (minutes, Method D)=0.54

EXAMPLE 2d

N-[2-(4-Chloro-phenyl)-2-morpholin-4-yl-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=359.2,t_(R) (minutes, Method F)=0.55

EXAMPLE 2e

2,3-Dichloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine. LCMS(MH⁺): m/z=448.1, t_(R) (minutes, Method B)=0.91

EXAMPLE 2f

2-Chloro-N-[2-(4-chloro-phenyl)-2-morpholin-4-yl-ethyl]-3-methyl-benzamide

From 2-chloro-3-methylbenzoic acid and2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺): m/z=393.2,t_(R) (minutes, Method F)=0.58

EXAMPLE 2g

2,3-Dichloro-N-[2-(6-chloro-3-pyridyl)-2-morpholino-ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(6-chloro-3-pyridyl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺):m/z=415.8, t_(R) (minutes, Method C)=1.15

EXAMPLE 2h

2,3-Dichloro-N-(2-morpholino-2-pyrimidin-5-yl-ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-morpholin-4-yl-2-pyrimidin-5-yl-ethylamine. LCMS (MH⁺): m/z=381.1,t_(R) (minutes, Method C)=0.92

EXAMPLE 2i

2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺):m/z=395.0, t_(R) (minutes, Method C)=0.94

EXAMPLE 2j

2,3-Dichloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine. LCMS(MH⁺): m/z=449.0, t_(R) (minutes, Method B)=0.95

EXAMPLE 2k

2,3-Dichloro-N-[2-(4,4-difluoro-piperidin-1-yl)-2-(4-fluoro-phenyl)-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and2-(4-fluoro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine. LCMS(MH⁺): m/z=431.2, t_(R) (minutes, Method D)=0.57

EXAMPLE 2l

2,3-dichloro-N-[2-(4,4-difluoro-1-piperidyl)-2-(4-methoxyphenyl)ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(4-methoxy-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine. LCMS(MH⁺): m/z=443.1, t_(R) (minutes, Method E)=1.81

EXAMPLE 2m

2,3-Dichloro-N-[2-(4,4-difluoro-1-piperidyl)-2-(6-fluoro-3-pyridyl)ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(6-fluoro-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine. LCMS(MH⁺): m/z=432.0, t_(R) (minutes, Method E)=2.33

EXAMPLE 2n

2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2-(6-fluoro-3-pyridyl)ethyl]benzamide

From 2-chlorobenzoic acid and2-(6-fluoro-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine. LCMS(MH⁺): m/z=398.1, t_(R) (minutes, Method E)=2.10

EXAMPLE 2o

2,3-Dichloro-N-[2-(4,4-difluoro-1-piperidyl)-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(6-(trifluoromethyl)-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.LCMS (MH⁺): m/z=482.0, t_(R) (minutes, Method E)=2.62

EXAMPLE 2p

2-Chloro-N-[2-(4,4-difluoro-1-piperidyl)-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

From 2-chlorobenzoic acid and2-(6-(trifluoromethyl)-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.LCMS (MH⁺): m/z=448.1, t_(R) (minutes, Method E)=2.30

EXAMPLE 2q

2,3-dichloro-N-(2-(4-chlorophenyl)-2-(1,4-oxazepan-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-chlorophenyl)-2-(1,4-oxazepan-4-yl)ethanamine. LCMS (MH+):m/z=429.0, t_(R) (minutes, Method H)=0.51

EXAMPLE 2r

2,3-dichloro-N-(2-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethanamine. LCMS (MH+): m/z=397.2,t_(R) (minutes, Method D)=0.54

EXAMPLE 2s

2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine. LCMS (MH+):m/z=379.2, t_(R) (minutes, Method D)=0.36

EXAMPLE 2t

2,6-difluoro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2,6-difluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine. LCMS (MH+):m/z=363.2, t_(R) (minutes, Method D)=0.40

EXAMPLE 2u

2,6-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine. LCMS (MH+):m/z=395.2, t_(R) (minutes, Method D)=0.45

EXAMPLE 2v

2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine. LCMS (MH+):m/z=379.2, t_(R) (minutes, Method D)=0.43

EXAMPLE 2x

2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=483.1, t_(R) (minutes, Method F)=2.56

EXAMPLE 2y

2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=449.1, t_(R) (minutes, Method F)=2.38

EXAMPLE 2z

2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=429.1, t_(R) (minutes, Method F)=1.83

EXAMPLE 2a1

2,3-dichloro-N-(2-(4,4-dimethylpiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-dimethylpiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=475.1, t_(R) (minutes, Method G)=2.23

EXAMPLE 2b1

2,3-dichloro-N-(2-(4-methoxypiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-methoxypiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=423.1, t_(R) (minutes, Method F)=2.04

EXAMPLE 2c1

2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine. LCMS (MH+):m/z=409.1, t_(R) (minutes, Method D)=0.40

EXAMPLE 2d1

2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine. LCMS (MH+):m/z=375.1, t_(R) (minutes, Method D)=0.33

EXAMPLE 2e1

2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine. LCMS (MH+):m/z=393.1, t_(R) (minutes, Method D)=0.35

EXAMPLE 2f1

2,6-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine. LCMS (MH+):m/z=409.1, t_(R) (minutes, Method D)=0.35

EXAMPLE 2g1

2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine. LCMS (MH+):m/z=393.1, t_(R) (minutes, Method D)=0.32

EXAMPLE 2h1

2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(3-methylpyrrolidin-1-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(3-methylpyrrolidin-1-yl)ethanamine. LCMS(MH+): m/z=393.1, t_(R) (minutes, Method D)=0.44

EXAMPLE 2i1

2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)ethanamine.LCMS (MH+): m/z=451.1, t_(R) (minutes, Method D)=0.64

EXAMPLE 2j 1

2,4-dichloro-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=449.1, t_(R) (minutes, Method D)=0.63

EXAMPLE 2k1

2,4-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=429.2, t_(R) (minutes, Method D)=0.61

EXAMPLE 2l1

2,3-dichloro-N-(2-(3-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(3-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=407.2, t_(R) (minutes, Method D)=0.49

EXAMPLE 2m1

2,3-dichloro-N-(2-(2-isopropylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-isopropylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=435.2, t_(R) (minutes, Method D)=0.51

EXAMPLE 2n1

2,3-dichloro-N-(2-(2-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=407.1, t_(R) (minutes, Method E)=0.49

EXAMPLE 2o1

N-(2-(2-azabicyclo[2.2.1]heptan-2-yl)-2-(2-methylpyrimidin-5-yl)ethyl)-2,3-dichlorobenzamide

From 2,3-dichlorobenzoic acid and2-(2-azabicyclo[2.2.1]heptan-2-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=405.2, t_(R) (minutes, Method D)=0.46

EXAMPLE 2p1

2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(dimethylamino)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and5-(2-amino-1-(4,4-difluoropiperidin-1-yl)ethyl)-N,N-dimethylpyrimidin-2-amine.LCMS (MH+): m/z=458.2, t_(R) (minutes, Method D)=0.57

EXAMPLE 2q1

2-chloro-3-fluoro-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=433.3, t_(R) (minutes, Method D)=0.57

EXAMPLE 2r1

2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and5-(2-amino-1-(4,4-difluoropiperidin-1-yl)ethyl)-1-methylpyridin-2(1H)-one.LCMS (MH+): m/z=323.0, t_(R) (minutes, Method E)=0.43

EXAMPLE 2s1

2,3-dichloro-N-(2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=427.0, t_(R) (minutes, Method F)=1.95

EXAMPLE 2t1

2,4-dichloro-N-(2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=427.0, t_(R) (minutes, Method F)=1.99

EXAMPLE 3a

(−)2,3-Dichloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

A mixture of2-Morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (200 mg,0.72 mmol), 2,3-dichlorobenzoic acid (138 mg, 0.726 mmol), HOBT (147 mg,1.09 mmol), EDCl.HCl (207 mg, 1.09 mmol) and DIPEA (281 mg, 2.18 mmol)in DMF (2mL) was stirred at room temperature overnight. The mixture waspurified by preparative HPLC directly to yield the racemic compound (150mg, yield: 46.3%).

The racemic mixture was separated into the two enantiomers bypreparative SFC to yield the title compound LCMS (MH⁺): m/z=448.0, t_(R)(minutes, Method E)=2.31. [α]_(D) ²⁰=−5.7 (c=2.28 mg/mL, CHCl₃)

And the corresponding enantiomer

EXAMPLE 3b

(+)2,3-Dichloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

LCMS (MH⁺): m/z=448.0, t_(R) (minutes, Method E)=2.31. [α]_(D) ²⁰=5.4(c=5.2 mg/mL, CHCl₃)

The following compounds were synthesised in a similar way:

EXAMPLE 3c

(−)2-Chloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]-3-(trifluoromethyl)benzamide

From 2-chloro-3-(trifluoromethyl)benzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine. LCMS(MH⁺): m/z=482.1, t_(R) (minutes, Method E)=2.43. [α]_(D) ²⁰=−6.67(c=1.2 mg/mL, CHCl₃)

EXAMPLE 3d

(+)2-Chloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]-3-(trifluoromethyl)benzamide

LCMS (MH⁺): m/z=482.1, t_(R) (minutes, Method E)=2.42. [α]_(D) ²⁰=5.83(c=1.2 mg/mL, CHCl₃)

EXAMPLE 3e

(−)2,3-Dichloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine. LCMS(MH⁺): m/z=449.0, t_(R) (minutes, Method E)=2.49. [α]_(D) ²⁰=−17.14(c=1.4 mg/mL, CHCl₃)

EXAMPLE 3f

(+)2,3-Dichloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

LCMS (MH⁺): m/z=449.0, t_(R) (minutes, Method E)=2.49. [α]_(D) ²⁰=17.47(c=1.66 mg/mL, CHCl₃)

EXAMPLE 3g

(−)2-Chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3-(trifluoromethyl)benzamide

From 2-chloro-3-(trifluoromethyl)benzoic acid and2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine. LCMS(MH⁺): m/z=483.1, t_(R) (minutes, Method E)=2.62. [α]_(D) ²⁰=−15.09(c=1.06 mg/mL, CHCl₃)

EXAMPLE 3h

(+)2-Chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3-(trifluoromethyl)benzamide

LCMS (MH⁺): m/z=483.1, t_(R) (minutes, Method E)=2.62. [α]_(D) ²⁰=15.04(c=1.33 mg/mL, CHCl₃)

EXAMPLE 3i

(−)2-Chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2-chlorobenzoic acid and2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine. LCMS(MH⁺): m/z=415.1, t_(R) (minutes, Method E)=2.30. [α]_(D) ²⁰=−16.0(c=2.00 mg/mL, CHCl₃)

EXAMPLE 3j

(+)2-Chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

LCMS (MH⁺): m/z=415.1, t_(R) (minutes, Method E)=2.30. [α]_(D) ²⁰=16.5(c=2.00 mg/mL, CHCl₃)

EXAMPLE 3k

(−)2-Fluoro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2-fluorobenzoic acid and2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine. LCMS(MH⁺): m/z=399.1, t_(R) (minutes, Method E)=2.27. [α]_(D) ²⁰=−16.9(c=1.6 mg/mL, CHCl₃)

EXAMPLE 3l

(+)2,3-Dichloro-N-[2-(6-methyl-3-pyridyl)-2-morpholino-ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(6-methyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺):m/z=394.0, t_(R) (minutes, Method E)=1.79. [α]_(D) ²⁰=8.3 (c=4.7 mg/mL,CHCl₃)

EXAMPLE 3m

(+)2-Chloro-3-methoxy-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

From 2-chloro-3-methoxybenzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine LCMS(MH⁺): m/z=444.2, t_(R) (minutes, Method E)=2.08. [α]_(D) ²⁰=7.5 (c=2.0mg/mL, CHCl₃)

EXAMPLE 3n

(−)2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-morpholin-4-yl-ethylamine. LCMS (MH⁺):m/z=395.1, t_(R) (minutes, Method E)=1.56. [α]_(D) ²⁰=−6.67 (c=0.9mg/mL, CHCl₃)

EXAMPLE 3o

(+)2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide

LCMS (MH⁺): m/z=395.1, t_(R) (minutes, Method E)=1.58. [α]_(D) ²⁰=6.9(c=0.87 mg/mL, CHCl₃)

EXAMPLE 3p

(+)2,6-Difluoro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

From 2,6-difluorobenzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine LCMS(MH⁺): m/z=416.2, t_(R) (minutes, Method E)=1.75. [α]_(D) ²⁰=7.9 (c=2.8mg/mL, CHCl₃)

EXAMPLE 3q

(+)2-Methoxy-N-[2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-benzamide

From 2-methoxybenzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine LCMS(MH⁺): m/z=410.2, t_(R) (minutes, Method E)=1.96. [α]_(D) ²⁰=24.8 (c=7.0mg/mL, CHCl₃).

EXAMPLE 3r

(−)2-Methoxy-N-[2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-benzamide

LCMS (MH⁺): m/z=410.2, t_(R) (minutes, Method E)=1.96. [α]_(D) ²⁰=−20.7(c=7.0 mg/mL, CHCl₃).

EXAMPLE 3s

(−)2-chloro-3-methoxy-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine LCMS(MH⁺): m/z=442.2, t_(R) (minutes, Method F)=2.10. [α]_(D) ²⁰=−8.0 (c=1.5mg/mL, CHCl₃).

EXAMPLE 3t

(−)2,6-difluoro-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2,6-difluorobenzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine LCMS(MH⁺): m/z=416.2, t_(R) (minutes, Method F)=1.73. [α]_(D) ²⁰=−7.5 (c=2.4mg/mL, CHCl₃).

EXAMPLE 3u

(+)2-chloro-6-fluoro-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine LCMS(MH⁺): m/z=432.2, t_(R) (minutes, Method F)=2.09. [α]_(D) ²⁰=12.1 (c=1.9mg/mL, CHCl₃).

EXAMPLE 3v

(−)2-chloro-6-fluoro-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH⁺): m/z=432.2, t_(R) (minutes, Method F)=2.38. [α]_(D) ²⁰=−12.5(c=2.0 mg/mL, CHCl₃).

EXAMPLE 3x

(+)2-chloro-5-(methylsulfonyl)-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-5-(methylsulfonyl)benzoic acid and2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine LCMS(MH⁺): m/z=492.1, t_(R) (minutes, Method F)=1.73. [α]_(D) ²⁰=5.8 (c=3.6mg/mL, CHCl₃).

EXAMPLE 3y

(−)2-chloro-5-(methylsulfonyl)-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH⁺): m/z=492.1, t_(R) (minutes, Method F)=1.74. [α]_(D) ²⁰=−5.8(c=3.8 mg/mL, CHCl₃).

EXAMPLE 3z

(+)2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH⁺): m/z=361.1,t_(R) (minutes, Method I)=1.48. [α]_(D) ²⁰=12.86 (c=2.8 mg/mL, CHCl₃).

EXAMPLE 3a1

(−)2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH⁺): m/z=361.1, t_(R) (minutes, Method I)=1.48. [α]_(D) ²⁰=−13.23(c=3.4 mg/mL, CHCl₃).

EXAMPLE 3b1

(+)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-(methylsulfonyl)benzamide

From 2-chloro-5-(methylsulfonyl)benzoic acid and2-(4-chlorophenyl)-2-morpholinoethanamine LCMS (MH⁺): m/z=457.1, t_(R)(minutes, Method F)=1.96. [α]_(D) ²⁰=18.3 (c=1.2 mg/mL, CHCl₃).

EXAMPLE 3c1

(−)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-(methylsulfonyl)benzamide

LCMS (MH⁺): m/z=457.1, t_(R) (minutes, Method F)=1.95. [α]_(D) ²⁰=−17.6(c=2.6 mg/mL, CHCl₃).

EXAMPLE 3d1

(+)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-cyanobenzamide

From 2-chloro-5-cyanobenzoic acid and2-(4-chlorophenyl)-2-morpholinoethanamine LCMS (MH⁺): m/z=404.1, t_(R)(minutes, Method F)=1.78. [α]_(D) ²⁰=5.7 (c=2.3 mg/mL, CHCl₃).

EXAMPLE 3e1

(−)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-cyanobenzamide

LCMS (MH⁺): m/z=404.1, t_(R) (minutes, Method F)=1.77. [α]_(D) ²⁰=−4.6(c=1.3 mg/mL, CHCl₃).

EXAMPLE 3f1

(−)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-(isopropylsulfonyl)benzamide

From 2-chloro-5-(isopropylsulfonyl)benzoic acid and2-(4-chlorophenyl)-2-morpholinoethanamine LCMS (MH⁺): m/z=485.1, t_(R)(minutes, Method F)=1.90. [α]_(D) ²⁰=−5.6 (c=3.56 mg/mL, CHCl₃).

EXAMPLE 3g1

(+)2-chloro-3-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=413.2, t_(R) (minutes, Method F)=1.75. [α]_(D) ²⁰=9.06 (c=3.2mg/mL, CHCl₃).

EXAMPLE 3h1

(−)2-chloro-3-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=413.2, t_(R) (minutes, Method F)=1.75. [α]_(D) ²⁰=−7.74(c=3.1 mg/mL, CHCl₃).

EXAMPLE 3i1

(+)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=413.2, t_(R) (minutes, Method F)=1.67. [α]_(D) ²⁰=13.56(c=4.5 mg/mL, CHCl₃).

EXAMPLE 3j1

(−)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=413.2, t_(R) (minutes, Method F)=1.67. [α]_(D) ²⁰=−10.21(c=4.8 mg/mL, CHCl₃).

EXAMPLE 3k1

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=467.1, t_(R) (minutes, Method F)=2.52. [α]_(D) ²⁰=9.33(c=1.5 mg/mL, CHCl₃).

EXAMPLE 3l1

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3-fluorobenzamide

LCMS (MH⁺): m/z=467.2, t_(R) (minutes, Method F)=2.52. [α]_(D) ²⁰=−8.57(c=1.4 mg/mL, CHCl₃).

EXAMPLE 3m1

(+)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=467.1, t_(R) (minutes, Method F)=2.5. [α]_(D) ²⁰=19.32(c=2.07 mg/mL, CHCl₃).

EXAMPLE 3n1

(−)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=467.1, t_(R) (minutes, Method F)=2.5. [α]_(D) ²⁰=−18.87(c=1.59 mg/mL, CHCl₃).

EXAMPLE 3o1

(+)2-chloro-3-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyridin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyridin-5-yl)ethanamine LCMS(MH⁺): m/z=412.2, t_(R) (minutes, Method F)=1.69. [α]_(D) ²⁰=13.24(c=3.4 mg/mL, CHCl₃).

EXAMPLE 3p1

(−)2-chloro-3-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyridin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=412.2, t_(R) (minutes, Method F)=1.70. [α]_(D) ²⁰=−13.71(c=3.5 mg/mL, CHCl₃).

EXAMPLE 3q1

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(6-methylpyridin-3-yl)ethyl)-6-fluorobenzamide

From 2-chloro-6-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyridin-5-yl)ethanamine LCMS(MH⁺): m/z=412.2, t_(R) (minutes, Method F)=1.64. [α]_(D) ²⁰=15.79(c=3.8 mg/mL, CHCl₃).

EXAMPLE 3r1

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(6-methylpyridin-3-yl)ethyl)-6-fluorobenzamide

LCMS (MH⁺): m/z=412.2, t_(R) (minutes, Method F)=1.64. [α]_(D) ²⁰=−15.14(c=3.5 mg/mL, CHCl₃).

EXAMPLE 3s1

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamineLCMS (MH⁺): m/z=466.1, t_(R) (minutes, Method F)=2.29. [α]_(D) ²⁰=10.97(c=3.1 mg/mL, CHCl₃).

EXAMPLE 3t1

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)-3-fluorobenzamide

LCMS (MH⁺): m/z=466.1, t_(R) (minutes, Method F)=2.30. [α]_(D) ²⁰=−9.69(c=3.2 mg/mL, CHCl₃).

EXAMPLE 3u1

(+)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamineLCMS (MH⁺): m/z=466.1, t_(R) (minutes, Method F)=2.27. [α]_(D) ²⁰=12.14(c=2.8 mg/mL, CHCl₃).

EXAMPLE 3v1

(−)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=466.1, t_(R) (minutes, Method F)=2.27. [α]_(D) ²⁰=−12.96(c=2.7 mg/mL, CHCl₃).

EXAMPLE 3x1

(+)2-chloro-3-methoxy-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine LCMS (MH⁺):m/z=445.1, t_(R) (minutes, Method F)=1.91. [α]_(D) ²⁰=6.4 (c=4.2 mg/mL,CHCl₃).

EXAMPLE 3z1

(−)2-chloro-3-methoxy-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=445.1, t_(R) (minutes, Method F)=1.91. [α]_(D) ²⁰=−8.25(c=4.0 mg/mL, CHCl₃).

EXAMPLE 3a2

(+)2-chloro-3-methoxy-N-(2-morpholino-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and2-morpholino-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine LCMS (MH⁺):m/z=424.2, t_(R) (minutes, Method F)=1.84. [α]_(D) ²⁰=5.3 (c=8.6 mg/mL,CHCl₃).

EXAMPLE 3b2

(−)2-chloro-3-methoxy-N-(2-morpholino-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=424.2, t_(R) (minutes, Method F)=1.85. [α]_(D) ²⁰=−4.3(c=7.9 mg/mL, CHCl₃).

EXAMPLE 3c2

(+)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and2-(4-chlorophenyl)-2-morpholinoethanamine LCMS (MH⁺): m/z=409.1, t_(R)(minutes, Method F)=1.79. [α]_(D) ²⁰=11.5 (c=7.2 mg/mL, CHCl₃).

EXAMPLE 3d2

(−)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-3-methoxybenzamide

LCMS (MH⁺): m/z=409.1, t_(R) (minutes, Method F)=1.78. [α]_(D) ²⁰=−12.2(c=6.6 mg/mL, CHCl₃).

EXAMPLE 3e2

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(4-fluorophenyl)ethyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(4-fluorophenyl)ethanamine LCMS (MH⁺):m/z=427.1, t_(R) (minutes, Method F)=1.55. [α]_(D) ²⁰=9.1 (c=8.1 mg/mL,CHCl₃).

EXAMPLE 3f2

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(4-fluorophenyl)ethyl)-3-methoxybenzamide

LCMS (MH⁺): m/z=427.2, t_(R) (minutes, Method F)=1.58. [α]_(D) ²⁰=−10.8(c=7.9 mg/mL, CHCl₃).

EXAMPLE 3g2

(+)2,3-dichloro-N-(2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=429.0, t_(R) (minutes, Method F)=2.52. [α]_(D) ²⁰=7.0 (c=4.8mg/mL, CHCl₃).

EXAMPLE 3h2

(−)2,3-dichloro-N-(2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=429.0, t_(R) (minutes, Method F)=2.52. [α]_(D) ²⁰=−7.6(c=6.0 mg/mL, CHCl₃).

EXAMPLE 3g2

(+)2-chloro-N-(2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=395.1, t_(R) (minutes, Method F)=2.32. [α]_(D) ²⁰=7.8 (c=5.0mg/mL, CHCl₃).

EXAMPLE 3h2

(−)2-chloro-N-(2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=395.1, t_(R) (minutes, Method F)=2.32. [α]_(D) ²⁰=−7.0(c=5.1 mg/mL, CHCl₃).

EXAMPLE 3g2

(+)2-chloro-3-fluoro-N-(2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=413.1, t_(R) (minutes, Method F)=2.41. [α]_(D) ²⁰=8.4 (c=5.0mg/mL, CHCl₃).

EXAMPLE 3h2

(−)2-chloro-3-fluoro-N-(2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=413.1, t_(R) (minutes, Method F)=2.42. [α]_(D) ²⁰=−7.8(c=4.6 mg/mL, CHCl₃).

EXAMPLE 3g2

(+)2-chloro-6-fluoro-N-(2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=413.1, t_(R) (minutes, Method F)=2.33. [α]_(D) ²⁰=10.5 (c=5.4mg/mL, CHCl₃).

EXAMPLE 3h2

(−)2-chloro-6-fluoro-N-(2-(3,3-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=413.1, t_(R) (minutes, Method F)=2.33. [α]_(D) ²⁰=−9.5(c=4.3 mg/mL, CHCl₃).

EXAMPLE 3i2

(+)2-chloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=377.1, t_(R) (minutes, Method F)=1.64. [α]_(D) ²⁰=3.0 (c=6.0mg/mL, CHCl₃).

EXAMPLE 3j2

(−)2-chloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=377.1, t_(R) (minutes, Method F)=1.63. [α]_(D) ²⁰=−3.06(c=6.2 mg/mL, CHCl₃).

EXAMPLE 3k2

(+)2,3-dichloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=411.1, t_(R) (minutes, Method F)=1.85. [α]_(D) ²⁰=3.14(c=5.73 mg/mL, CHCl₃).

EXAMPLE 3l2

(−)2,3-dichloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=411.1, t_(R) (minutes, Method F)=1.85. [α]_(D) ²⁰=−3.32(c=6.03 mg/mL, CHCl₃).

EXAMPLE 3m2

(+)2,6-dichloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=411.1, t_(R) (minutes, Method F)=1.70. [α]_(D) ²⁰=9.83 (c=6.0mg/mL, CHCl₃).

EXAMPLE 3n2

(−)2,6-dichloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=411.1, t_(R) (minutes, Method F)=1.69. [α]_(D) ²⁰=−10.0(c=5.1 mg/mL, CHCl₃).

EXAMPLE 3o2

(+)2-chloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=431.1, t_(R) (minutes, Method F)=1.90. [α]_(D) ²⁰=13.1(c=2.6 mg/mL, CHCl₃).

EXAMPLE 3p2

(−)2-chloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=431.1, t_(R) (minutes, Method F)=1.91. [α]_(D) ²⁰=−11.5(c=2.7 mg/mL, CHCl₃).

EXAMPLE 3q2

(+)2,3-dichloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=465.0, t_(R) (minutes, Method F)=2.39. [α]_(D) ²⁰=6.4(c=2.8 mg/mL, CHCl₃).

EXAMPLE 3r2

(−)2,3-dichloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method F)=2.10. [α]_(D) ²⁰=−6.6(c=3.8 mg/mL, CHCl₃).

EXAMPLE 3s2

(+)2,6-dichloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method F)=2.00. [α]_(D) ²⁰=12.2(c=2.3 mg/mL, CHCl₃).

EXAMPLE 3t2

(−)2,6-dichloro-N-(2-(4-fluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method F)=1.99. [α]_(D) ²⁰=−12.7(c=1.5 mg/mL, CHCl₃).

EXAMPLE 3u2

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethanamineLCMS (MH⁺): m/z=383.1, t_(R) (minutes, Method F)=1.70. [α]_(D) ²⁰=8.6(c=1.8 mg/mL, CHCl₃).

EXAMPLE 3v2

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)benzamide

LCMS (MH⁺): m/z=383.1, t_(R) (minutes, Method F)=1.70. [α]_(D) ²⁰=−7.1(c=1.8 mg/mL, CHCl₃).

EXAMPLE 3u2

(+)2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethanamineLCMS (MH⁺): m/z=417.0, t_(R) (minutes, Method F)=1.91. [α]_(D) ²⁰=11.1(c=2.4 mg/mL, CHCl₃).

EXAMPLE 3v2

(−)2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)benzamide

LCMS (MH⁺): m/z=417.0, t_(R) (minutes, Method F)=1.91. [α]_(D) ²⁰=−11.5(c=2.3 mg/mL, CHCl₃).

EXAMPLE 3u2

(+)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethanamineLCMS (MH⁺): m/z=417.0, t_(R) (minutes, Method F)=1.75. [α]_(D) ²⁰=7.9(c=4.9 mg/mL, CHCl₃).

EXAMPLE 3v2

(−)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)benzamide

LCMS (MH⁺): m/z=417.0, t_(R) (minutes, Method F)=1.76. [α]_(D) ²⁰=−8.7(c=4.0 mg/mL, CHCl₃).

EXAMPLE 3u2

(+)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)benzamide

From 2,3-dichloro-5-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethanamineLCMS (MH⁺): m/z=435.0, t_(R) (minutes, Method F)=1.97. [α]_(D) ²⁰=12.7(c=3.7 mg/mL, CHCl₃).

EXAMPLE 3v2

(−)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)benzamide

LCMS (MH⁺): m/z=435.0, t_(R) (minutes, Method F)=1.97. [α]_(D) ²⁰=−11.3(c=3.7 mg/mL, CHCl₃).

EXAMPLE 3x2

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=479.1, t_(R) (minutes, Method F)=2.73. [α]_(D) ²⁰=4.22(c=3.0 mg/mL, CHCl₃).

EXAMPLE 3y2

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3-methoxybenzamide

LCMS (MH⁺): m/z=479.1, t_(R) (minutes, Method F)=2.73. [α]_(D) ²⁰=−3.95(c=3.8 mg/mL, CHCl₃).

EXAMPLE 3z2

(+)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=483.0, t_(R) (minutes, Method F)=2.88. [α]_(D) ²⁰=4.85(c=2.2 mg/mL, CHCl₃).

EXAMPLE 3a3

(−)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=483.0, t_(R) (minutes, Method F)=2.85. [α]_(D) ²⁰=−5.76(c=2.2 mg/mL, CHCl₃).

EXAMPLE 3b3

(+)2,6-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,6-dichloro-5-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=501.0, t_(R) (minutes, Method F)=295. [α]_(D) ²⁰=6.33(c=2.0 mg/mL, CHCl₃).

EXAMPLE 3c3

(−)2,6-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=501.0, t_(R) (minutes, Method F)=2.95. [α]_(D) ²⁰=−8.0(c=2.0 mg/mL, CHCl₃).

EXAMPLE 3d3

(+)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichloro-5-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=501.1, t_(R) (minutes, Method F)=2.75. [α]_(D) ²⁰=2.94(c=4.2 mg/mL, CHCl₃).

EXAMPLE 3e3

(−)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=501.1, t_(R) (minutes, Method F)=2.75. [α]_(D) ²⁰=−3.33(c=3.8 mg/mL, CHCl₃).

EXAMPLE 3f3

(+)2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(piperidin-1-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(piperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS (MH⁺):m/z=359.2, t_(R) (minutes, Method F)=1.47. [α]_(D) ²⁰=6.67 (c=2.8 mg/mL,CHCl₃).

EXAMPLE 3g3

(−)2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(piperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=359.2, t_(R) (minutes, Method F)=1.47. [α]_(D) ²⁰=−5.04(c=2.38 mg/mL, CHCl₃).

EXAMPLE 3h3

(+)2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(piperidin-1-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(piperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS (MH⁺):m/z=393.2, t_(R) (minutes, Method F)=1.68. [α]_(D) ²⁰=5.70 (c=4.21mg/mL, CHCl₃).

EXAMPLE 3i3

(−)2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(piperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=393.1, t_(R) (minutes, Method F)=1.69. [α]_(D) ²⁰=−2.48(c=4.56 mg/mL, CHCl₃).

EXAMPLE 3j3

(+)2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=429.1, t_(R) (minutes, Method F)=2.19. [α]_(D) ²⁰=7.18(c=4.32 mg/mL, CHCl₃).

EXAMPLE 3k3

(−)2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=429.1, t_(R) (minutes, Method F)=2.20. [α]_(D) ²⁰=−8.18(c=4.89 mg/mL, CHCl₃).

EXAMPLE 3l3

(+)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=429.1, t_(R) (minutes, Method F)=2.30. [α]_(D) ²⁰=10.73(c=8.0 mg/mL, CHCl₃).

EXAMPLE 3m3

(−)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=429.1, t_(R) (minutes, Method F)=2.31. [α]_(D) ²⁰=−7.1(c=5.5 mg/mL, CHCl₃).

EXAMPLE 3n3

(+)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichloro-5-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=447.1, t_(R) (minutes, Method F)=2.54. [α]_(D) ²⁰=6.7 (c=3.2mg/mL, CHCl₃).

EXAMPLE 3o3

(−)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=447.1, t_(R) (minutes, Method F)=2.53. [α]_(D) ²⁰=−5.5(c=3.4 mg/mL, CHCl₃).

EXAMPLE 3p3

(+)2,6-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,6-dichloro-5-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=447.0, t_(R) (minutes, Method F)=2.18. [α]_(D) ²⁰=5.63 (c=3.2mg/mL, CHCl₃).

EXAMPLE 3q3

(−)2,6-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=447.0, t_(R) (minutes, Method F)=2.17. [α]_(D) ²⁰=−3.96(c=3.2 mg/mL, CHCl₃).

EXAMPLE 3r3

(+)2-chloro-3-methoxy-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=425.1, t_(R) (minutes, Method F)=1.99. [α]_(D) ²⁰=8.56 (c=4.4mg/mL, CHCl₃).

EXAMPLE 3s3

(−)2-chloro-3-methoxy-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=425.1, t_(R) (minutes, Method F)=1.83. [α]_(D) ²⁰=−7.8(c=4.4 mg/mL, CHCl₃).

EXAMPLE 3t3

(+)2-chloro-3-(difluoromethoxy)-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-(difluoromethoxy)benzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=461.2, t_(R) (minutes, Method F)=2.44. [α]_(D) ²⁰=25.19(c=2.62 mg/mL, CHCl₃).

EXAMPLE 3u3

(−)2-chloro-3-(difluoromethoxy)-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=461.1, t_(R) (minutes, Method F)=2.44. [α]_(D) ²⁰=−23.23(c=1.65 mg/mL, CHCl₃).

EXAMPLE 3v3

(+)2,3-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH⁺):m/z=431.1, t_(R) (minutes, Method F)=2.36. [α]_(D) ²⁰=14.88 (c=2.71mg/mL, CHCl₃).

EXAMPLE 3x3

(−)2,3-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH⁺): m/z=431.1, t_(R) (minutes, Method F)=2.37. [α]_(D) ²⁰=−11.93(c=2.85 mg/mL, CHCl₃).

EXAMPLE 3y3

(+)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH⁺):m/z=397.1, t_(R) (minutes, Method F)=1.90. [α]_(D) ²⁰=12.72 (c=1.73mg/mL, CHCl₃).

EXAMPLE 3z3

(−)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH⁺): m/z=397.1, t_(R) (minutes, Method F)=1.90. [α]_(D) ²⁰=−11.70(c=1.68 mg/mL, CHCl₃).

EXAMPLE 3a4

(+)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH⁺):m/z=415.1, t_(R) (minutes, Method F)=2.24. [α]_(D) ²⁰=16.38 (c=3.54mg/mL, CHCl₃).

EXAMPLE 3b4

(−)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH^(')): m/z=415.1, t_(R) (minutes, Method F)=2.23. [α]_(D)²⁰=−13.82 (c=4.56 mg/mL, CHCl₃).

EXAMPLE 3c4

(+)2-chloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamineLCMS (MH⁺): m/z=421.2, t_(R) (minutes, Method F)=2.36. [α]_(D) ²⁰=26.88(c=6.2 mg/mL, CHCl₃).

EXAMPLE 3d4

(−)2-chloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=421.2, t_(R) (minutes, Method F)=2.35. [α]_(D) ²⁰=−28.02(c=4.7 mg/mL, CHCl₃).

EXAMPLE 3e4

(+)2,3-dichloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamineLCMS (MH⁺): m/z=455.1, t_(R) (minutes, Method F)=2.41. [α]_(D) ²⁰=27.06(c=11.0 mg/mL, CHCl₃).

EXAMPLE 3f4

(−)2,3-dichloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=455.1, t_(R) (minutes, Method F)=2.42. [α]_(D) ²⁰=−28.03(c=10.0 mg/mL, CHCl₃).

EXAMPLE 3g4

(+)2,6-dichloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamineLCMS (MH⁺): m/z=455.0, t_(R) (minutes, Method F)=2.31. [α]_(D) ²⁰=25.50(c=6.6 mg/mL, CHCl₃).

EXAMPLE 3h4

(−)2,6-dichloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=455.1, t_(R) (minutes, Method F)=2.30. [α]_(D) ²⁰=−27.65(c=5.8 mg/mL, CHCl₃).

EXAMPLE 3i4

(+)2-chloro-6-fluoro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamineLCMS (MH⁺): m/z=439.2, t_(R) (minutes, Method F)=2.40. [α]_(D) ²⁰=27.66(c=7.1 mg/mL, CHCl₃).

EXAMPLE 3j4

(−)2-chloro-6-fluoro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=439.1, t_(R) (minutes, Method F)=2.40. [α]_(D) ²⁰=−26.27(c=7.0 mg/mL, CHCl₃).

EXAMPLE 3k4

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=409.2, t_(R) (minutes, Method F)=2.34. [α]_(D) ²⁰=20.94(c=7.21 mg/mL, CHCl₃).

EXAMPLE 3l4

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=409.2, t_(R) (minutes, Method F)=2.34. [α]_(D) ²⁰=−19.15(c=7.99 mg/mL, CHCl₃).

EXAMPLE 3m4

(−)2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=443.1, t_(R) (minutes, Method F)=2.56. [α]_(D) ²⁰=23.67(c=7.73 mg/mL, CHCl₃).

EXAMPLE 3n4

(−)2,3-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=443.1, t_(R) (minutes, Method F)=2.55. [α]_(D) ²⁰=−23.24(c=7.4 mg/mL, CHCl₃).

EXAMPLE 3o4

(+)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethanamine

LCMS (MH⁺): m/z=443.1, t_(R) (minutes, Method F)=2.44. [α]_(D) ²⁰=17.52(c=6.45 mg/mL, CHCl₃).

EXAMPLE 3p4

(−)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=443.1, t_(R) (minutes, Method F)=2.44. [α]_(D) ²⁰=−18.95(c=6.28 mg/mL, CHCl₃).

EXAMPLE 3q4

(+)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=427.2, t_(R) (minutes, Method F)=2.37. [α]_(D) ²⁰=21.82(c=7.15 mg/mL, CHCl₃).

EXAMPLE 3r4

(−)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=427.2, t_(R) (minutes, Method F)=2.38. [α]_(D) ²⁰=−21.79(c=7.02 mg/mL, CHCl₃).

EXAMPLE 3s4

(+)2,4-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=483.1, t_(R) (minutes, Method F)=2.95. [α]_(D) ²⁰=11.6(c=3.7 mg/mL, CHCl₃).

EXAMPLE 3t4

(−)2,4-dichloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=483.1, t_(R) (minutes, Method F)=2.95. [α]_(D) ²⁰=−14.4(c=4.0 mg/mL, CHCl₃).

EXAMPLE 3u4

(+)2-chloro-4-methoxy-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-4-methoxybenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=479.2, t_(R) (minutes, Method F)=3.03. [α]_(D) ²⁰=11.1(c=3.0 mg/mL, CHCl₃).

EXAMPLE 3v4

(−)2-chloro-4-methoxy-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=479.1, t_(R) (minutes, Method F)=3.04. [α]_(D) ²⁰=−13.6(c=3.0 mg/mL, CHCl₃).

EXAMPLE 3x4

(+)2,4-dichloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,4-dichloro-6-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=501.0, t_(R) (minutes, Method F)=3.01. [α]_(D) ²⁰=22.8(c=3.2 mg/mL, CHCl₃).

EXAMPLE 3y4

(−)2,4-dichloro-6-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=501.0, t_(R) (minutes, Method F)=3.01. [α]_(D) ²⁰=−23.4(c=3.0 mg/mL, CHCl₃).

EXAMPLE 3z4

(+)2-chloro-3,4-dimethoxy-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3,4-dimethoxybenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=509.1, t_(R) (minutes, Method F)=2.77. [α]_(D) ²⁰=23.3(c=3.6 mg/mL, CHCl₃).

EXAMPLE 3a5

(−)2-chloro-3,4-dimethoxy-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=509.1, t_(R) (minutes, Method F)=2.78. [α]_(D) ²⁰=−19.2(c=3.5 mg/mL, CHCl₃).

EXAMPLE 3b5

(+)2,6-dichloro-4-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,6-dichloro-4-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=501.1, t_(R) (minutes, Method F)=3.17. [α]_(D) ²⁰=19.64(c=2.24 mg/mL, CHCl₃).

EXAMPLE 3c5

(−)2,6-dichloro-4-fluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=501.1, t_(R) (minutes, Method F)=3.17. [α]_(D) ²⁰=−19.73(c=2.23 mg/mL, CHCl₃).

EXAMPLE 3d5

(+)2-chloro-4,6-difluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-4,6-difluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=485.1, t_(R) (minutes, Method F)=3.12. [α]_(D) ²⁰=14.40(c=2.43 mg/mL, CHCl₃).

EXAMPLE 3e5

(−)2-chloro-4,6-difluoro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=485.1, t_(R) (minutes, Method F)=3.12. [α]_(D) ²⁰=−12.21(c=2.13 mg/mL, CHCl₃).

EXAMPLE 3f5

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-6-fluoro-3-methoxybenzamide

From 2-chloro-3-methoxy-6-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=497.1, t_(R) (minutes, Method F)=3.05. [α]_(D) ²⁰=18.30(c=4.48 mg/mL, CHCl₃).

EXAMPLE 3g5

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-6-fluoro-3-methoxybenzamide

LCMS (MH⁺): m/z=497.1, t_(R) (minutes, Method F)=3.05. [α]_(D) ²⁰=−16.07(c=4.48 mg/mL, CHCl₃).

EXAMPLE 3h5

(+)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)-3-(trifluoromethoxy)benzamide

From 2-chloro-3-(trifluoromethoxy)benzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS(MH⁺): m/z=479.1, t_(R) (minutes, Method F)=2.63. [α]_(D) ²⁰=16.0 (c=6.0mg/mL, CHCl₃).

EXAMPLE 3i5

(−)2-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)-3-(trifluoromethoxy)benzamide

LCMS (MH⁺): m/z=479.1, t_(R) (minutes, Method F)=2.63. [α]_(D) ²⁰=−13.3(c=4.9 mg/mL, CHCl₃).

EXAMPLE 3j5

(+)2-chloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyridin-5-yl)ethanamineLCMS (MH⁺): m/z=430.1, t_(R) (minutes, Method F)=2.45. [α]_(D) ²⁰=4.10(c=1.95 mg/mL, CHCl₃).

EXAMPLE 3k5

(−)2-chloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=430.1, t_(R) (minutes, Method F)=2.45. [α]_(D) ²⁰=−6.06(c=1.98 mg/mL, CHCl₃).

EXAMPLE 3l5

(+)2,3-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyridin-5-yl)ethanamineLCMS (MH⁺): m/z=464.1, t_(R) (minutes, Method F)=2.65. [α]_(D) ²⁰=3.06(c=3.27 mg/mL, CHCl₃).

EXAMPLE 3m5

(−)2,3-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=464.1, t_(R) (minutes, Method F)=2.65. [α]_(D) ²⁰=−4.71(c=2.76 mg/mL, CHCl₃).

EXAMPLE 3n5

(+)2,6-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyridin-5-yl)ethanamineLCMS (MH⁺): m/z=464.1, t_(R) (minutes, Method F)=2.57. [α]_(D) ²⁰=12.02(c=2.08 mg/mL, CHCl₃).

EXAMPLE 3o5

(−)2,6-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=464.1, t_(R) (minutes, Method F)=2.57. [α]_(D) ²⁰=−11.47(c=2.18 mg/mL, CHCl₃).

EXAMPLE 3p5

(+)2,4-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyridin-5-yl)ethanamineLCMS (MH⁺): m/z=464.1, t_(R) (minutes, Method F)=2.69. [α]_(D) ²⁰=11.56(c=1.47 mg/mL, CHCl₃).

EXAMPLE 3q5

(−)2,4-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=464.1, t_(R) (minutes, Method F)=2.70. [α]_(D) ²⁰=−11.90(c=2.52 mg/mL, CHCl₃).

EXAMPLE 3r5

(+)2-chloro-3-methoxy-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyridin-5-yl)ethanamineLCMS (MH⁺): m/z=460.1, t_(R) (minutes, Method F)=2.45. [α]_(D) ²⁰=4.07(c=2.95 mg/mL, CHCl₃).

EXAMPLE 3s5

(−)2-chloro-3-methoxy-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=460.1, t_(R) (minutes, Method F)=2.45. [α]_(D) ²⁰=−5.07(c=2.96 mg/mL, CHCl₃).

EXAMPLE 3t5

(+)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyridin-5-yl)ethanamineLCMS (MH⁺): m/z=448.1, t_(R) (minutes, Method F)=2.54. [α]_(D) ²⁰=10.75(c=1.86 mg/mL, CHCl₃).

EXAMPLE 3u5

(−)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=448.1, t_(R) (minutes, Method F)=2.54. [α]_(D) ²⁰=−13.72(c=2.55 mg/mL, CHCl₃).

EXAMPLE 3v5

(+)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=431.1, t_(R) (minutes, Method F)=2.53. [α]_(D) ²⁰=17.6(c=3.5 mg/mL, CHCl₃).

EXAMPLE 3x5

(−)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=431.1, t_(R) (minutes, Method I)=2.23. [α]_(D) ²⁰=−17.0(c=3.7 mg/mL, CHCl₃).

EXAMPLE 3y5

(+)2,3-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method F)=2.74. [α]_(D) ²⁰=17.7(c=3.7 mg/mL, CHCl₃).

EXAMPLE 3z5

(−)2,3-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method F)=2.74. [α]_(D) ²⁰=−17.9(c=4.5 mg/mL, CHCl₃).

EXAMPLE 3a6

(+)2,6-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method I)=2.36. [α]_(D) ²⁰=19.5(c=3.6 mg/mL, CHCl₃).

EXAMPLE 3b6

(−)2,6-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method I)=2.36. [α]_(D) ²⁰=−18.3(c=3.8 mg/mL, CHCl₃).

EXAMPLE 3c6

(+)2,4-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method G)=2.16. [α]_(D) ²⁰=18.9(c=3.6 mg/mL, CHCl₃).

EXAMPLE 3d6

(−)2,4-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method G)=2.16. [α]_(D) ²⁰=−16.5(c=4.0 mg/mL, CHCl₃).

EXAMPLE 3e6

(+)2-chloro-3-methoxy-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=461.1, t_(R) (minutes, Method I)=2.26. [α]_(D) ²⁰=19.6(c=3.7 mg/mL, CHCl₃).

EXAMPLE 3f6

(−)2-chloro-3-methoxy-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=461.1, t_(R) (minutes, Method I)=2.26. [α]_(D) ²⁰=−20.2(c=4.0 mg/mL, CHCl₃).

EXAMPLE 3g6

(+)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4,4-difluoropiperidin-1-yl)-2-(2-(difluoromethyl)pyrimidin-5-yl)ethanamineLCMS (MH⁺): m/z=449.1, t_(R) (minutes, Method E)=2.62. [α]_(D) ²⁰=16.4(c=3.8 mg/mL, CHCl₃).

EXAMPLE 3h6

(−)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide

LCMS (MH⁺): m/z=449.1, t_(R) (minutes, Method E)=2.63. [α]_(D) ²⁰=−14.1(c=3.8 mg/mL, CHCl₃).

EXAMPLE 3i6

(+)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH⁺):m/z=427.1, t_(R) (minutes, Method E)=2.06. [α]_(D) ²⁰=11.11 (c=1.8mg/mL, CHCl₃).

EXAMPLE 3j6

(−)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)-3-methoxybenzamide

LCMS (MH⁺): m/z=427.1, t_(R) (minutes, Method E)=2.05. [α]_(D) ²⁰=−10.78(c=1.67 mg/mL, CHCl₃).

EXAMPLE 3k6

(+)2,4-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2,4-dichlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH⁺):m/z=431.1, t_(R) (minutes, Method F)=2.32. [α]_(D) ²⁰=15.0 (c=1.0 mg/mL,CHCl₃).

EXAMPLE 3l6

(−)2,4-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH⁺): m/z=431.1, t_(R) (minutes, Method E)=2.31. [α]_(D) ²⁰=−15.74(c=1.08 mg/mL, CHCl₃).

EXAMPLE 3m6

(+)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)-3-(trifluoromethyl)benzamide

From 2-chloro-3-(trifluoromethyl)benzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH⁺):m/z=465.1, t_(R) (minutes, Method E)=2.42. [α]_(D) ²⁰=17.0 (c=1.0 mg/mL,CHCl₃).

EXAMPLE 3n6

(−)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)-3-(trifluoromethyl)benzamide

LCMS (MH⁺): m/z=465.1, t_(R) (minutes, Method E)=2.42. [α]_(D) ²⁰=−19.42(c=1.03 mg/mL, CHCl₃).

EXAMPLE 4

2-(2-(1,1-Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine(34 mg, 0.044 mmol, 40% pure) and 2,3-dichlorobenzoyl chloride (65 mg,0.31 mmol), was dissolved in anhydrous THF (4400 mg, 5 ml, 61.0 mmol),DIPEA (111 mg, 0.15 ml, 0.859 mmol) was added and stirred over night.The solution was concentrated and purified by column chromatography onsilica gel (petroleum ether: EtOAc=1:0 to 0:1) followed by HPLC, toafford2,3-dichloro-N-(2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide(10 mg, 47% yield). LCMS (MH⁺): m/z=479.3, t_(R) (minutes, MethodD)=0.71.

EXAMPLE 5

2,3-Dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(4-oxopiperidin-1-yl)ethyl)benzamide

To a solution of2,3-dichloro-N-(2-(4-hydroxypiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide(130 mg, 0.32 mmol) in DCM (5 mL) was added 4A molecular sieves (1.3 g),NMO (205 mg, 1.75 mmol) and TPAP (2.2 mg). The mixture was stiffed atroom temperature overnight. The resulting mixture was filtered. Thefiltrate was washed with water, dried over Na2SO4 and concentrated. Theresidue was purified by preparative TLC (EtOAc:MeOH=100:3) to give2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(4-oxopiperidin-1-yl)ethyl)benzamide(31 mg, yield: 24%) as a white solid. ¹HNMR (CDCl₃ 400 MHz): δ 8.59 (s,2H), 7.56 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.49 (dd, J=7.6 Hz, 1.6 Hz, 1H),7.34-7.27 (m, 1H), 6.63 (br, 1H), 4.08-3.82 (m, 3H), 2.95-2.82 (m, 2H),2.79-2.65 (m, 5H), 2.55-2.40 (m, 4H). LCMS (MH+): m/z=425.0, t_(R)(minutes, Method F)=1.75

The following compounds were synthesisied in a similar way:

EXAMPLE 51

2,4-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(-1-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and2-(4-oxopiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=425.1, t_(R) (minutes, Method F)=2.01

EXAMPLE 6

P2X₇ Binding Assay

This example illustrates representative assays for use in evaluating thetest compounds for antagonist activity. Compounds of the presentinvention were tested in vitro for their ability to act as antagoniststo the P2X₇ receptor.

Screening assays to determine P2X₇ receptor antagonism are well known tothe person skilled in the art. Functional assays, such as secondmessenger assays, and cytokine measurement assays done in vitro are alsowell known in the art and may be used to assess the specific binding andcellular activity of P2X₇ receptor compounds.

In Vitro Assay Example

Cell culture: 293 HEK cells, stably transfected with plasmids capable ofexpressing human P2X₇ receptor, were cultured by standard methods. Cellswere plated to cell density of approximately 15,000 cells/well in384-well assay plates (50 μl/well) with 1.5% low serum media (DMEM, 1.5%BCS, 1% L-glut (2 mM), 1% P/S).

293 HEK cells, stably transfected with plasmids capable of expressingrat or mouse P2X₇ receptor, were cultured by standard methods. Cellswere plated to cell density of approximately 15,000 cells/well in384-well assay plates (50 μl/well) with 1.5% low serum media (DMEM, 1.5%FBS, 1% L-glut (2 mM), 10 mM HEPES, 1% P/S). Cells were plated 24 hoursprior to assay. Cells expressing human, rat or mouse P2X₇ receptor wereassayed in the following manner.

Fluorescent Imaging Plate Reader (FLIPR) assay: Briefly, 293-human ormouse P2X₇ stable cells were incubated in sucrose buffer, pH 7.4 [KCl (5mM), NaH₂PO₄.2H₂O (9.6 mM), HEPES (25 mM), sucrose (280 mM), glucose (5mM), CaCl₂ (0.5 mM), and probenecid (0.1425 g in 3 mL 1N NaOH was addedfor 500 mL solution)] in 384-well plates.

293-rat P2X₇ stable cells were incubated in HHPB (pH 7.4) [consisting ofHank's BSS (1×); HEPES (pH 7.4) (20 mM) (Sigma); probenecid (0.710 g/5mL 1N NaOH) (Sigma); and BSA (0.05%) (Roche) which was added after thepH had been adjusted] in 384-well plates. Fluo-4 NW dye mix (MolecularProbes, Inc., Eugene, Oreg., USA) was prepared in buffer (seemanufacturer's instructions). Cell plates were removed from the 37° C.incubator, the media discarded and then 30 μL of dye was added to eachwell. Plates were placed in the 37° C., non-CO₂ incubator for 30 minutesand then room temperature for 30 minutes.

Two sets of drug plates were prepared: A) Mixtures of compound plusagonist were prepared as follows, in order to determine close response:BzATP: 11 point ½ log, diluted in buffer, starting from 1 mM. Testingcompounds: 11 point ½ log, diluted in 2% DMSO buffer starting from 10μM. B) Agonist only mixture was prepared with BzATP at a singleconcentration in buffer (concentration determined by dose response).

Compound mixtures (A) were added to assay plates containing cells andplaced at room temperature for 30 minutes, then BzATP (B) was added.Fluorescence was read using the Tetra FLIPR® (Molecular Devices, Inc.,Sunnyvale, Calif., USA) and IC₅₀ values were calculated by standardmethods to determine antagonist activity.

Assay for stimulating IL1β release from THP-1 cells: THP-1 cells (TheGlobal Bioresource Center; ATCC #: TIB-202™) were differentiated byincubation with 10 ng/mL IFN-gamma (Sigma, Cat#: I3265) in T150 plates,at a cell density of 0.5 E⁶ cells/mL, in RPMI1640 media (ATCC, Cat#30-2001) with 10% FBS and 1% P/S for 48 hours. The cells then werestimulated with 100 ng/mL LPS (Sigma, Cat#: L4516) in serum free CTLTest media (Sigma Cat#: CTLT-005), without L-glutamine and antibiotics,for 3 hours. Test compounds (antagonists) were added and incubated for30 minutes. BzATP (at final concentration of 1 mM) was added andincubated for 30 minutes.

Cell plates were centrifuged at 3000 rpm for 5 minutes and thesupernatants were immediately collected for AlphaLISA® immunoassay(PerkinElmer Inc., Waltham, Mass., USA; Catalog No. AL220C) or aliquotedand stored at <−20 C. The AlphaLISA® immunoassay was performed accordingto the manufacturer's instructions.

TABLE 1 Exemplified IC₅₀ values of compounds of the invention: Chemicalname P2X7 IC₅₀ (nM) 2-Chloro-5-methyl-N-(2-morpholin-4-yl-2- 3000pyridin-3-yl-ethyl)-benzamide 2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-2700 pyridin-4-yl-ethyl)-benzamide2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin- 1100 3-yl-ethyl)-benzamide2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin- 750 4-yl-ethyl)-benzamide2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin- 2700 3-yl-ethyl)-benzamide2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin- 1400 4-yl-ethyl)-benzamide2,3-Dichloro-N-[2-(4-fluoro-phenyl)-2- 11 morpholin-4-yl-ethyl]benzamide2,3-Dichloro-N-[2-(4-methoxy-phenyl)-2- 350piperidin-1-yl-ethyl]-benzamide 2,3-Dichloro-N-[2-(4-methoxy-phenyl)-2-13 morpholin-4-yl-ethyl]-benzamideN-[2-(4-Fluoro-phenyl)-2-morpholin-4-yl- 20ethyl]-2,3-dimethyl-benzamide N-[2-(4-Methoxy-phenyl)-2-piperidin-1-yl-420 ethyl]-2,3-dimethyl-benzamideN-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl- 47ethyl]-2,3-dimethyl-benzamide 2-Chloro-N-[2-(4-fluoro-phenyl)-2- 21morpholin-4-yl-ethyl]-5-methyl-benzamide2-Chloro-N-[2-(4-methoxy-phenyl)-2- 650piperidin-1-yl-ethyl]-5-methyl-benzamide2-Chloro-N-[2-(4-methoxy-phenyl)-2- 59morpho1in-4-yl-ethyl]-5-methyl-benzamideN-[2-(4-Fluoro-phenyl)-2-morpholin-4-yl- 110 ethyl]-2-methyl-benzamideN-[2-(4-Methoxy-phenyl)-2-piperidin-1-yl- 3900 ethyl]-2-methyl-benzamide N-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl- 500ethyl]-2-methyl-benzamide 2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-p- 38tolyl-ethyl)-benzamide N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro- 2piperidin-1-yl)-ethyl]-2-methyl-benzamideN-[2-(4-Chloro-phenyl)-2-(4,4-difluoro- 3.6piperidin-1-yl)-ethyl]-2,3-dimethyl- benzamide2,3-Dichloro-N-[2-(4-chloro-phenyl)-2-(4,4- 46difluoro-piperidin-1-yl)-ethyl]-benzamide2,3-Dichloro-N-[(S)-2-(4-chloro-phenyl)-2- 0.62morpholin-4-yl-ethyl]-benzamide2,3-Dichloro-N-[2-(6-cyclopropyl-pyridin-3- 8.2yl)-2-morpholin-4-yl-ethyl]-benzamideN-[(S)-2-(4-Chloro-phenyl)-2-morpholin-4- 9.3yl-ethyl]-2-methyl-benzamide 2,3-dichloro-N-[2-morpholino-2-[6- 4.6(trifluoromethyl)-3-pyridyl]ethyl]benzamide2-Chloro-N-[(S)-2-(4-chloro-phenyl)-2- 0.53morpholin-4-yl-ethyl]-3-methyl-benzamide2,3-dichloro-N-[2-(6-chloro-3-pyridyl)-2- 3.9 morpholino-ethyl]benzamide2,3-dichloro-N-(2-morpholino-2-pyrimidin-5- 28 yl-ethyl)benzamide2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)- 212-molpholino-ethyl]benzamide 2,3-dichloro-N-[2-morpholino-2-[2- 8.2(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide2,3-Dichloro-N-[2-(4,4-difluoro-piperidin-1- 0.33yl)-2-(4-fluoro-phenyl)-ethyl]-benzamide(−)2-chloro-N-[2-morpholino-2-[6- 12(trifluoromethyl)-3-pyridyl]ethyl]-3- (trifluoromethyl)benzamide(+)2-chloro-N-[2-morpholino-2-[6- 24(trifluoromethyl)-3-pyridyl]ethyl]-3- (trifluoromethyl)benzamide(−)2,3-dichloro-N-[2-morpholino-2-[2- 3.2 (trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide (+)2,3-dichloro-N-[2-morpholino-2-[2- 4.8(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-N-[2-morpholino-2-[2- 9.9(trifluoromethyl)pyrimidin-5-yl]ethyl]-3- (trifluoromethyl)benzamide(+)2-chloro-N-[2-morpholino-2-[2- 17(trifluoromethyl)pyrimidin-5-yl]ethyl]-3- (trifluoromethyl)benzamide(−)2,3-dichloro-N-[2-morpholino-2-[6- 2(trifluoromethyl)-3-pyridyl]ethyl]benzamide(+)2,3-dichloro-N-[2-morpholino-2-[6- 5.5(trifluoromethyl)-3-pyridyl]ethyl]benzamide2,3-dichloro-N-[2-(4,4-difluoro-1-piperidyl)- 0.62-(4-methoxyphenyl)ethyl]benzamide2,3-dichloro-N-[2-(4,4-difluoro-1-piperidyl)- 0.892-(6-fluoro-3-pyridyl)ethyl]benzamide2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2-(6- 4fluoro-3-pyridyl)ethyl]benzamide2,3-dichloro-N-[2-(4,4-difluoro-1-piperidyl)- 1.32-[6-(trifluoromethyl)-3- pyridyl]ethyl]benzamide2-chloro-N-[2-(4,4-difluoro-1-pipetidyl)-2-[6- 1.8(trifluoromethyl)-3-pyridyl]ethyl]benzamide(−)2-chloro-N-[2-morpholino-2-[2- 15 (trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide (+)2-chloro-N-[2-morpholino-2-[2- 30(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-fluoro-N-[2-morpholino-2-[2- 44 (trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide (+)2,3-dichloro-N-[2-(6-methyl-3-pyridyl)-2- 44morpholino-ethyl]benzamide 2,3-Dichloro-N-[2-(4-chloro-phenyl)-2- 17[1,4]oxazepan-4-yl-ethyl]-benzamide(−)2-chloro-3-methoxy-N-(2-morpholino-2-(6- 3.5(trifluoromethyl)pyridin-3-yl)ethyl)benzamide(+)2-chloro-3-methoxy-N-[2-morpholino-2- 14 [6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide (−)2-chloro-6-fluoro-N-(2-morpholino-2-(6- 6.1(trifluoromethyl)pyridin-3-yl)ethyl)benzamide(+)2-chloro-6-fluoro-N-[2-morpholino-2-[6- 32(trifluoromethyl)-3-pyridyl]ethyl]benzamide(−)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- 110morpholino-ethyl]benzamide (+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2-630 morpholino-ethyl]benzamide(−)2,3-dichloro-N-[2-(2-methylpyrimidin-5- 27yl)-2-morpholino-ethyl]benzamide(+)2,3-dichloro-N-[2-(2-methylpyrimidin-5- 69yl)-2-morpholino-ethyl]benzamide (−)2,6-difluoro-N-[2-morpholino-2-6-480 (trifluoromethyl)-3-pyridyl]ethyl]benzamide(+)2,6-difluoro-N-[2-morpholino-2-6- 29(trifluoromethyl)-3-pyridyl]ethyl]benzamide(−)2-chloro-5-methylsulfonyl-N-[2- 51morpholino-2-[6-(trifluoromethyl)-3- pyridyl]ethyl]benzamide(+)2-chloro-5-methylsulfonyl-N-[2- 71morpholino-2-[6-(trifluoromethyl)-3- pyridyl]ethyl]benzamide(+)2-chloro-N-[2-(4-chlorophenyl)-2- 180morpholino-ethyl]-5-methylsulfonyl- benzamide(−)2-chloro-N-[2-(4-chlorophenyl)-2- 65morpholino-ethyl]-5-methylsulfonyl- benzamide2,3-Dichloro-N-[2-(4-chloro-phenyl)-2- 1800pyrrolidin-1-yl-ethyl]-benzamide (−)2-methoxy-N-[2-morpholino-2-[6- 21(trifluoromethyl)-3-pyridyl]ethyl]benzamide(+)-2-methoxy-N-(2-morpholino-2-(6- 98(trifluoromethyl)pyridin-3-yl)ethyl]benzamide(+)2-chloro-N-[2-(4-chlorophenyl)-2- 23morpholino-ethyl]-5-cyano-benzamide (−)2-chloro-N-[2-(4-chlorophenyl)-2-110 morpholino-ethyl]-5-cyano-benzamide2,3-dichloro-N-[2-(4,4-difluoro-1-piperidyl)- 0.652-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2-[2- 2.8(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide2,3-dichloro-N-[2-(4,4-difluoro-1-piperidyl)- 4.32-(2-methylpyrimidin-5-yl)ethyl]benzamide(−)2-chloro-N-[2-(4-chlorophenyl)-2- 47morpholino-ethyl]-5-isopropylsulfonyl- benzamide2-Chloro-3-fluoro-N-[2-(2-methyl-pyrimidin- 12005-yl)-2-morpholin-4-yl-ethyl]-benzamide2,6-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 1202-morpholinoethyl)benzamide 2-chloro-6-fluoro-N-(2-(2-methylprimidin-5-590 yl)-2-morpholinoethyl)benzamide(+)2-chloro-N-[2-4,4-difluoro-1-piperidyl)-2- 13(2-methylpyrimidin-5-yl)ethyl]benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 24(2-methylpyrimidin-5-yl)ethyl]benzamide(+)2-chloro-N-[2,(4,4,-difluoro-1-piperidyl)-2- 1.7[6-(tifluoromethyl)-3-pyridyl]ethyl]-3-fluoro- benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 5.7[6-(tifluoromethyl)-3-pyridyl]ethyl]-3-fluoro- benzamide(+)2-chloro-N-[2-(4,4,-difluoro-1-piperidyl)-2- 0.62[6-(tifluoromethyl)-3-pyridyl]ethyl]-6-fluoro- benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 3[6-(trifluoromethyl)-3-pyridyl]ethyl]-6-fluoro- benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 33(6-methyl-3-pyridyl)ethyl]-3-fluoro- benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 21(6-methyl-3-pridypethyl]-3-fluoro- benzamide(+)2-chloro-N-[2,(4,4-difluoro-1-piperidyl)-2- 110(6-methyl-3-pyridyl)ethyl]-6-fluoro- benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 22(6-methyl-3-pyridyl)ethyl]-6-fluoro- benzamide2,6-difluoro-N-(2-(2-methylpyrimidin-5-yl)- 11002-morpholinoethyl)benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 15(2-methylpyrimidin-5-yl)ethyl]-3-fluoro- benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 19(2-methylpyrimidin-5-yl)ethyl]-3-fluoro- benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 19(2-methylpyrimidin-5-yl)ethyl]-6-fluoro- benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 32(2-methylpyrimidin-5-yl)ethyl]-6-fluoro- benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 8.3[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6- fluoro-benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 8.2[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6- fluoro-benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 1.7[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3- fluoro-benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 4.2[2-(trifluoromethyl)pyrimidin-5-yl)ethyl]-3- fluoro-benzamide2,3-dichloro-N-[2-(4,4-dimethyl-1-piperidyl)- 25002-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide2-chloro-N-[2-(4,4-dimethyl-1-piperidyl)-2- 3600[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3- fluoro-benzamide2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 292-(1,4-oxazepan-4-yl)ethyl)benzamide2,6-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 7402-(1,4-oxazepan-4-yl)ethyl)benzamide2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5- 820yl)-2-(1,4-oxazepan-4-yl)ethyl)benzamide2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2- 680(1,4-oxazepan-4-yl)ethyl)benzamide2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5- 330yl)-2-(1,4-oxazepan-4-yl)ethyl)benzamide(−)2-chloro-3-methoxy-N-[2-morpholino-2-[2- 8.2(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2-chloro-3-methoxy-N-[2-morpholino-2- 16[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)3-methoxy-2-methyl-N[2-morpholino-2- 16[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide(+)3-methoxy-2-methyl-N-[2-morpholino-2- 13 [6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide (−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2-2.6 (4-fluorophenyl)ethyl]-3-methoxy-benzamide (+)2-chl oro-N-[2-(4,4-difluoro-1-piperidyl)-2- 2.6(4-fluorophenyl]ethyl]-3-methoxy-benzamide2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 10002-(3-methylpyrrolidin-1-yl)ethyl)benzamide 2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 2.6 2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)ethyl)benzamide (−)2-chloro-N-[2-(4-chlorophenyl)-2- 1.5morpholino-ethyl]-3-methoxy-benzamide(+)2-chloro-N-[2-(4-chlorophenyl)-2- 4.2morpholino-ethyl]-3-methoxy-benzamide(+)2-chloro-N-[2-(3,3-difluoro-1-piperidyl)-2- 53(2-methylpyrimidin-5-yl)ethyl]-6-fluoro- benzamide(−)2-chloro-N-[2-(3,3-difluoro-1-piperidyl)-2- 280(2-methylpyrimidin-5-yl)ethyl]-6-fluoro- benzamide(+)2-chloro-N-[2-(3,3-difluoro-1piperidyl)-2- 100(2-methylpyrimidin-5-yl)ethyl]-3-fluoro- benzamide(−)2-chloro-N-[2-(3,3-difluoro-1-piperidyl)-2- 41(2-methylpyrimidin-5-yl)ethyl]-3-fluoro- benzamide(+)2,3-dichloro-N-[2-(3,3-difluoro-1- 14piperidyl)-2-(2-methylpyrimidin-5- yl)ethyl]benzamide (+)2-chloro-N-[2-(3,3-difluoro-1-piperidyl)-2- 85(2-methylpyrimidin-5-yl)ethyl]benzamide(−)2-chloro-N-[2-(3,3-difluoro-1-piperidyl)-2- 28 (2-methylprimidin-5-yl)ethyl]benzamide(+)2-chloro-N-[2-(4-fluoro-1-piperidyl)-2-[2- 15(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-N-[2-(4-fluoro-1-piperidyl)-2-[2- 13(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2,6-dichloro-N-[2-(4-fluoro-1-piperidyl)-2- 6.1[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2,6-dichloro-N-[2-(4-fluoro-1-piperidyl)-2- 15[2-(tifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2,3-dichloro-N-[2-(4-fluoro-1-piperidyl)-2- 3.5[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2,3-dichloro-N-[2-(4-fluoro-1-piperidyl)-2- 4.7[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2,6-diehloro-N-[2-(4-fluoro-1-piperidyl)-2- 9.6(2-methylpyrimidin-5-yl)ethyl]benzamide(−)2,6-dichloro-N-[2-(4-fluoro-1-piperidyl)-2- 53(2-methylpyrimidin-5-yl)ethyl]benzamide(+)2,3-dichloro-N-[2-(4-fluoro-1-piperidyl)-2- 6.5(2-methylpyrimidin-5-yl)ethyl]benzamide(−)2,3-dichloro-N-[2-(4-fluoro-1-piperidyl)-2- 14(2-methylpyrimidin-5-yl)ethyl]benzamide(+)2-chloro-N-[2-(4-f1uoro-1-piperidyl)-2-(2- 50methylpyrimidin-5-yl)ethyl]benzarnide(−)2-chloro-N-[2-(4-fluoro-1-piperidyl)-2-(2- 45methylpyrimidin-5-yl)ethyl]benzamide 2,4-dichloro-N-(2-morpholino-2-(2-12 (trifluoromethyl)pyrimidin-5- yl)ethyl)benzamide(−)2,3-dichloro-N-[2-(4,4-difluoro-1- 25piperidyl)-2-(1-methylpyrazol-4- yl)ethyl]benzamide(+)2,3-dichloro-N-[2-(4,4-difluoro-1- 12piperidyl)-2-(1-methylpyrazol-4- ypethyl]benzamide(−)2,3-dichloro-N-2-(4,4-difluoro-1- 26piperidyl)-2-(1-methylpyrazol-4-ypethyl]-5- fluoro-benzamide(+)2,3-dichloro-N-[2-(4,4-difluoro-1- 34piperidyl)-2-(1-methylpyrazol-4-ypethyl]-5- fluoro-benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 230(1-methylpyrazol-4-yl)ethyl]benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 180(1-methylpyrazol-4-yl)ethyl]benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 4.8[2-(tifluoromethyl)pyrimidin-5-yl]ethyl]-3- methoxy-benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 3.6[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3- methoxy-benzamide(−)2,6-dichloro-N-[2-(4,4-difluoro-1- 6.9piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5- yl)ethyl]benzamide(+)2,6-dichloro-N-[2-(4,4-difluoro-1- 4.7piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2,6-dichloro-N-[2-(4,4-difluoro-1- 4.9piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3-fluoro-benzamide (+)2,6-dichloro-N-[2-(4,4-difluoro-1- 7.1piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3-fluoro-benzamide(−)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- 120(1-piperidyl)ethyl]benzamide(+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- 59(1-piperidyl)ethyl]benzamide (−)2,3-dichloro-N-[2-(2-methylpyrimidin-5-21 yl)-2-(1-piperidyl)ethyl]benzamide(+)2,3-dichloro-N-[2-(2-methylpyrimidin-5- 8.9yl)-2-(1-piperidypethyl]benzamide (−)2,3-dichloro-N-[2-(4,4-difluoro-1-2.2 piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl)ethyl]-5-fluoro-benzamide (+)2,3-dichloro-N-[2-(4,4-difluoro-1- 4.9piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-5-fluoro-benzamide (−)2,6-dichloro-N-[2-(4,4-difluoro-1- 44piperidyl)-2-(1-methylpyrazol-4- yl)ethyl]benzamide(+)2,6-dichloro-N-[2-(4,4-difluoro-1- 56 piperidyl)-2-(1-methylpyrazo1-4- yl)ethyl]benzamide (−)2-chloro-N-[2-[2- 15(difluoromethyl)pyrimidin-5-yl]-2- morpholino-ethyl]benzamide(+)2-chloro-N-[2-[2- 60 (difluoromethyl)pyrimidin-5-yl]-2-morpholino-ethyl]benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 11(2-methylpyrimidin-5-yl)ethyl]-3-methoxy- benzamide (+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 12(2-methylpyrimidin-5-yl)ethyl]-3-methoxy- benzamide(−)2,6-dichloro-N-[2-(4,4-difluoro-1- 37piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]- 3-fluoro-benzamide(+)2,6-dichloro-N-[2-(4,4-difluoro-1- 25piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]- 3-fluoro-benzamide(−)2,6-dichloro-N-[2-(4,4-difluoro-1- 22piperidyl)-2-(2-methylpyrimidin-5- yl)ethyl]benzamide(+)2,6-dichloro-N-[2-(4,4-difluoro-1- 19piperidyl)-2-(2-methylpyrimidin-5- yl)ethyl]benzamide(−)2,3-dichloro-N-[2-(4,4-difluoro-1- 14piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]- 5-fluoro-benzamide(+)2,3-dichloro-N-[2-(4,4-difluoro-1- 5.1piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]- 5-fluoro-benzamide(−)2,3-dichloro-N-[2-(4,4-difluoro-1- 5.8piperidyl)-2-(2-methylpyrimidin-5- yl)ethyl]benzamide(+)2,3-dichloro-N-[2-(4,4-difluoro-1- 3.2piperidyl)-2-(2-methylpyrimidin-5- yl)ethyl]benzamide(−)2,3-dichloro-N-[2-[2- 9.6 (difluoromethyl)pyrimidin-5-yl]-2-morpholino-ethyl]benzamide (+)2,3-dichloro-N-[2-[2- 3.9(difluoromethyl)pyrimidin-5-yl]-2- morpholino-ethyl]benzamide(−)2-chloro-N-[2-[2- 38 (difluoromethyl)pyrimidin-5-yl]-2-morpholino-ethyl]-3-fluoro-benzamide (+)2-chloro-N-[2-[2- 4.8(difluoromethyl)pyrimidin-5-yl]-2- morpholino-ethyl]-3-fluoro-benzamide(−)2-chloro-N-[2-(2-cyclopropylpyrimidin-5- 7.6 yl)-2-(4,4-difluoro-1-piperidyl)ethyl]benzamide (+)2-chloro-N-[2-(2-cyclopropylpyrimidin-5- 3yl)-2-(4,4-difluoro-1- piperidypethyl]benzamide (−)2,6-dichloro-N-[2-(2-5.8 cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-1-piperidyl)ethyl]benzamide (+)2,6-dichloro-N-[2-(2- 5.3cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-1- piperidyl)ethyl]benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 17(2-ethylpyrimidin-5-yl)ethyl]benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 12(2-ethylpyrimidin-5-yl)ethyl]benzamide(−)2,6-dichloro-N-[2-(4,4-difluoro-1- 27 piperidyl)-2-(2-ethylpyrimidin-5- yl)ethyl]benzamide(+)2,6-dichloro-N-[2-(4,4-difluoro-1- 15piperidyl)-2-(2-ethylpyrimidin-5- yl)ethyl]benzamide(−)2-chloro-3-(difluoromethoxy)-N-[2-(4, 4- 37 difluoro-1-piperidyl)-2-(2-methylpyrimidin-5- yl)ethyl]benzamide(+)2-chloro-3-(difluoromethoxy)-N-[2-(4,4- 7difluoro-1-piperidyl)-2-(2-methylpyrimidin-5- yl)ethyl]benzamide(−)2,3-dichloro-N-[2-(4,4-difluoro-1- 4.9piperidyl)-2-(2-ethylpyrimidin-5- yl)ethyl]benzamide(+)2,3-dichloro-N-[2-(4,4-difluoro-1- 2.6piperidyl)-2-(2-ethylpyrimidin-5- yl)ethyl]benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 36(2-ethylpyrimidin-5-yl)ethyl]-6-fluoro- benzamide (+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 14(2-ethylpyrimidin-5-yl)ethyl]-6-fluoro- benzamide(−)2,3-dichloro-N-[2-(2- 3.5cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-1- piperidyl)ethyl]benzamide(+)2,3-dichloro-N-[2-(2- 4.3cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-1- piperidyl)ethyl]benzamide(−)2-chloro-N-[2-(2-cyclopropylpyrimidin-5- 11yl)-2-(4,4-difluoro-1-piperidypethyl]-6- fluoro-benzamide(+)2-chloro-N-[2-(2-cyclopropylpyrimidin-5- 9.9yl)-2-(4,4-difluoro-1-piperidypethyl]-6- fluoro-benzamide2,4-dichloro-N-(2-(4,4-difluoropiperidin-1- 44yl)-2-(2-methylpyrimidin-5- yl)ethyl)benzamide2,3-dichloro-N-(2-(3-methylpiperidin-1-yl)-2- 170(2-methylpyrimidin-5-yl)ethyl)benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 31[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4,6- difluoro-benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 9.4[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4,6- difluoro-benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 31[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6- fluoro-3-methoxy-benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 8.9[2-(tifluoromethyl)pyrimidin-5-yl]ethyl]-6- fluoro-3-methoxy-benzamide2,3-dichloro-N-( 2-(2-isopropylpiperidin-1-yl)- 19002-(2-methylpyrimidin-5-yl)ethyl)benzamide2,3-dichloro-N-(2-(4,4-difluoropiperidin-1- 6.6 yl)-2-(2-(dimethylamino)pyrimidin-5- yl)ethyl)benzamideN-(2-(2-azabicyclo[2.2.1]heptan-2-yl)-2-(2- 3200methylpyrimidin-5-yl)ethyl)-2,3- dichlorobenzamide2,3-dichloro-N-(2-(2-methylpiperidin-1-yl)-2- 310(2-methylpyrimidin-5-yl)ethyl)benzamide(−)2,4-dichloro-N-[2-(4,4-difluoro-1- 6.4piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2,4-dichloro-N-[2-(4,4-difluoro-1- 5.6piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2,4-dichloro-N-[2-(4,4-difluoro-1- 6.5piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6-fluoro-benzamide (+)2,4-dichloro-N-[2-(4,4-difluoro-1- 4.7piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6-fluoro-benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 2.2[2-(tifluoromethyl)pyrimidin-5-yl]ethyl]-4- methoxy-benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 4.3[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4- methoxy-benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 7.8[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3,4- dimethoxy-benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 14[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3,4- dimethoxy-benzamide2,3-dichloro-N-[2-(4-methoxy-1-piperidyl)-2- 3800(2-methylpyrimidin-5-yl)ethyl]benzamide(−)2,6-dichloro-N-[2-(4,4-difluoro-1- 15piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4-fluoro-benzamide (+)2,6-dichloro-N-[2-(4,4-difluoro-1- 7.5piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4-fluoro-benzamide(−)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 40(2-methylpyrimidin-5-yl)ethyl]-3- (trifluoromethoxy)benzamide(+)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2- 21(2-methylpyrimidin-5-yl)ethyl]-3- (trifluoromethoxy)benzamide2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)- 192-(4-oxo-1-piperidyl)ethyl]benzamide2,4-dichloro-N-[2-(2-methylpyrimidin-5-yl)- 9702-(4-oxo-1-piperidyl)ethyl]benzamide 2,3-dichloro-N-[2-(4-chloro-1-piperidyl)-2-(2- 5.7 methylpyrimidin-5-ypethyl]benzamide2,4-dichloro-N-[2-(4-chloro-1-piperidyl)-2-(2- 280methylpyrimidin-5-yl)ethyl]benzamide2-chloro-3-fluoro-N-(2-morpholino-2-(2- 11 (trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (+)2-chloro-N-[2-[6-(difluoromethyl)-3- 9pyridyl]-2-(4,4-difluoro-1- piperidyl)ethylibenzamide(−)2-chloro-N-[2-[6-(difluoromethyl)-3- 12 pyridyl]-2-(4,4-difluoro-1-piperidyl)ethyl]benzamide (+)2,3-dichloro-N-[2-[6-(difluoromethyl)-3-2.4 pyridyl]-2-(4,4-difluoro-1- piperidyl)ethyl]benzamide(−)2,3-dichloro-N-[2-[6-(difluoromethyl)-3- 4.2pyridyl]-2-(4,4-difluoro-1- piperidyl)ethyl]benzamide(+)2,6-dichloro-N-[2-[6-(difluoromethyl)-3- 8.7pyridyl]-2-(4,4-difluoro-1- piperidyl)ethyl]benzamide(−)2,6-dichloro-N-[2-[6-(difluoromethyl)-3- 5.5pyridyl]-2-(4,4-difluoro-1- piperidyl)ethyl]benzamide(+)2-chloro-N-[2-[6-(difluoromethyl)-3- 2.3pyridyl]-2-(4,4-difluoro-1-piperidyl)ethyl]-3- methoxy-benzamide(−)2-chloro-N-[2-[6-(difluoromethyl)-3- 1.9pyridyl]-2-(4,4-difluoro-1-piperidyl)ethyl]-3- methoxy-benzamide2,3-Dichloro-N-[2-(4-chloro-phenyl)-2- 0.6morpholin-4-yl-ethyl]-benzamide

What is claimed:
 1. A compound of formula I:

wherein R¹ is pyrazinyl, optionally substituted with one or moreC₁₋₆alkyl, halogen, hydroxy, C₁₋₄fluoroalkyl, C₃₋₆cycloalkyl,C₁₋₆alkoxy, C₁₋₆fluoroalkoxy, cyano or —SO₂R⁷; wherein R^(2a) and R^(2b)combine with the nitrogen to which they are attached to formpiperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolo, imidazo,azetidinyl, 6 to 10 membered spiro(heterocyclyl), homomorpholinyl,homopiperidinyl or homopiperazinyl, each of which is optionallysubstituted with one or more C₁₋₆ alkyl, C₁₋₆alkenyl, C₃₋₆-cycloalkyl,C₁₋₆alkoxy, oxo, —NR⁵R⁶ or fluorines; wherein R³ is halogen,C₁₋₄fluoroalkyl, cyano, cyclopropyl, C₁₋₄alkyloxy, C₁₋₄fluoroalkyloxy,—SO₂R⁷, —NR⁵R⁶ or C₁₋₆alkyl; wherein R⁴ is halogen, C₁₋₆alkyl,C₁₋₄fluoroalkyl, cyano, —SO₂R⁸, —NR⁵R⁶, C₁₋₆alkoxy, C₁₋₄fluoroalkoxy orC₃₋₆cycloalkyl; wherein R⁵ and R⁶ independently of each other arehydrogen or C₁₋₆alkyl; wherein R⁷ is C₁₋₆alkyl, C₃₋₆cycloalkyl,C₁₋₄fluoroalkyl and wherein n is 0-3; or a pharmaceutically acceptablesalt thereof.
 2. The compound or pharmaceutically acceptable saltthereof of claim 1, wherein R^(2a) and R^(2b) combine with the nitrogento which they are attached to form optionally substituted piperazinyl.3. The compound or pharmaceutically acceptable salt thereof of claim 1,wherein R^(2a) and R^(2b) combine with the nitrogen to which they areattached to form optionally substituted piperidinyl.
 4. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein R^(2a) andR^(2b) combine with the nitrogen to which they are attached to formoptionally substituted morpholinyl.
 5. The compound or pharmaceuticallyacceptable salt thereof of claim 1, wherein R^(2a) and R^(2b) combinewith the nitrogen to which they are attached to form optionallysubstituted pyrrolidinyl.
 6. The compound or pharmaceutically acceptablesalt thereof of claim 1, wherein R^(2a) and R^(2b) combine with thenitrogen to which they are attached to form optionally substitutedpyrrolo.
 7. The compound or pharmaceutically acceptable salt thereof ofclaim 1, wherein R^(2a) and R^(2b) combine with the nitrogen to whichthey are attached to form optionally substituted imidazo.
 8. Thecompound or pharmaceutically acceptable salt thereof of claim 1, whereinR^(2a) and R^(2b) combine with the nitrogen to which they are attachedto form optionally substituted 6 to 10 membered spiro(heterocyclyl). 9.The compound or pharmaceutically acceptable salt thereof of claim 1,wherein R^(2a) and R^(2b) combine with the nitrogen to which they areattached to form optionally substituted homomorpholinyl.
 10. Thecompound or pharmaceutically acceptable salt thereof of claim 1, whereinR^(2a) and R^(2b) combine with the nitrogen to which they are attachedto form optionally substituted homopiperidinyl.
 11. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein R^(2a) andR^(2b) combine with the nitrogen to which they are attached to formoptionally substituted homopiperazinyl.
 12. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein R^(2a) andR^(2b) combine with the nitrogen to which they are attached to formoptionally substituted azetidinyl.
 13. The compound or pharmaceuticallyacceptable salt thereof of claim 1, wherein R³ is chlorine, methyl ortrifluoromethyl.
 14. The compound or pharmaceutically acceptable saltthereof of claim 1, wherein n is
 0. 15. The compound or pharmaceuticallyacceptable salt thereof of claim 1, wherein n is
 1. 16. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein n is
 2. 17.The compound or pharmaceutically acceptable salt thereof of claim 1,wherein R⁴ is fluorine, chlorine, C₁₋₃alkyl, C₁₋₄ fluoroalkyl, cyano,C₁₋₃alkoxy or C₁₋₄fluoroalkoxy.
 18. A pharmaceutical compositioncomprising the compound or pharmaceutically acceptable salt thereof ofclaim 1 and a pharmaceutically acceptable carrier.